DOCX format

Risk Assessment and

Risk Management Plan for

DIR 140

Consultation Version

Clinical trial of a genetically modified virus for treatment of liver cancer

Applicant: Clinical Network Services Pty Ltd

December 2015

Office of the Gene Technology Regulator

PAGE INTENTIONALLY LEFT BLANK


Summary of the Risk Assessment and Risk

Management Plan

(Consultation Version) for

Licence Application No. DIR 140

Introduction

The Gene Technology Regulator (the Regulator) has received a licence application for dealings with a genetically modified (GM) virus developed for cancer therapy. Clinical Network

Services Pty Ltd (CNS) is seeking approval under the Gene Technology Act 2000 (the Act) to conduct a Phase 3 clinical trial of the GM virus in patients with advanced liver cancer. Because trial participants would be inoculated with the GM virus in a hospital setting then allowed to return home for the duration of the observation period, the application qualifies as a limited and controlled release application under the Act.

Clinical trials in Australia must be conducted in accordance with requirements of the

Therapeutic Goods Act 1989 , which is administered by the Therapeutic Goods Administration

(TGA). Clinical trials of therapeutic products that are experimental and under development are regulated by the TGA through the Clinical Trial Exemption (CTX) scheme or the Clinical Trial

Notification (CTN) scheme. CNS has indicated that they will submit a Clinical Trial

Notification to the TGA. Clinical trials are also required to have approval from the Human

Research Ethics Committee at each trial site before the trial commences, and must be conducted in accordance with the National Statement on the Ethical Conduct in Research

Involving Humans.

As part of Australia’s integrated approach to the regulation of gene technology, regulation under the Act is not intended to override or duplicate the regulatory oversight of agencies that have responsibility for genetically modified organisms (GMOs) or GM products based on their intended use. The TGA, the trial sponsor, the investigators and the Human Research Ethics

Committee (HREC) at each trial site all have roles to play in ensuring participants’ safety under the Therapeutic Goods Act 1989 . Therefore, the Regulator focuses primarily on risks posed to people other than those participating in the clinical trial, and to the environment.

The Regulator has prepared a science-based Risk Assessment and Risk Management Plan

(RARMP) for this application, which concludes that the proposed clinical trial poses negligible to low risks to human health and safety and the environment. Draft licence conditions have been proposed for the clinical trial to manage the low risks and to restrict the spread and persistence of the GMO in the environment. The Regulator invites submissions on the

RARMP, including draft licence conditions, to inform the decision on whether or not to issue a licence.

Summary i


The application

Application number

Applicant

Project title

Parent organism

Introduced genes and modified traits

Proposed release dates

Proposed location

Primary purpose

DIR 140

Clinical Network Services (CNS) Pty Ltd

Clinical trial of a genetically modified virus for treatment of liver cancer 1

Vaccinia virus, New York City Board of Health (NYCBH) vaccine strain

 inactivation of viral thymidine kinase (TK) gene (human therapeutic – attenuation)

 insertion of human Granulocyte-Macrophage Colony-Stimulating Factor

(hGM-CSF) gene (human therapeutic - enhanced immune response)

 insertion of bacterial lacZ gene from Escherichia coli (E. coli) (reporter gene expression)

The clinical trial is anticipated to occur over a 12 month period, commencing in

2016. A total period of 5 years has been requested to accommodate follow-up studies, if required.

For administration by medical professionals in hospitals throughout Australia

(specific locations have not yet been selected, but would be chosen so as to provide access to patients with liver cancer).

To assess the effectiveness and safety of the GMO as a treatment for advanced liver cancer when provided in conjunction with a standard treatment, compared with the standard treatment alone.

CNS has proposed a clinical trial of a live GM vaccinia virus (VACV) intended to preferentially kill cancer cells and trigger an immune response against the tumour. Up to 50 adult volunteers with advanced hepatocellular carcinoma (HCC), a common type of liver cancer, would be treated with the genetically modified organism (GMO). The purpose of the trial is to assess the effectiveness and safety of the GMO as a treatment for advanced HCC when provided in conjunction with a standard treatment, compared with the standard treatment alone.

The parent organism, VACV, is a member of the Poxvirus family, infects a range of mammalian species and is mildly pathogenic in humans. It is not known to be circulating in any human population but was used world-wide as a vaccine to protect against smallpox infection. VACV has attracted recent interest as a potential cancer therapeutic as it is thought to show a natural selectivity for cancer cells without causing significant adverse effects in the patient.

The GMO is based on the Dryvax

TM

smallpox vaccine (Wyeth Laboratories), which was used extensively in the USA during the smallpox eradication campaign in the 1960s and 70s.

Dryvax

TM

was prepared from the New York City Board of Health (NYCBH) vaccinia strain and contains a mixture of closely related viruses of relatively low pathogenicity. The GMO is derived from a single clone isolated from this mixture.

1 The title of the licence application submitted by Clinical Network Services (CNS) Pty Ltd is ‘A

Phase 3 Randomized, Open-Label Study Comparing Pexa Vec (Vaccinia GM CSF / Thymidine Kinase-

Deactivated Virus) Followed by Sorafenib Versus Sorafenib in Patients with Advanced Hepatocellular

Carcinoma (HCC) Without Prior Systemic Therapy (JX594-HEP024)’.

Summary ii


The GMO has been modified so as to enhance its specificity for cancer cells. The vaccinia thymidine kinase ( TK ) gene, encoding a thymidine kinase enzyme required for DNA synthesis and viral replication, has been disrupted by insertion of the GM-CSF and lacZ genes. As a result, the GMO can only reproduce in host cells which produce their own TK. TK is expressed at low levels during normal cell division and at higher levels in most cancer cells, but not in non-dividing cells. Thus, the GMO is expected to replicate well in tumours while displaying attenuation in normal tissues, leading to preferential destruction of cancer cells.

A single copy of the human GM-CSF gene has been inserted within the viral TK gene, so as to promote an anti-cancer immune response. hGM-CSF is a naturally occurring cytokine that encourages the proliferation of certain types of immune cell. When tumour cells are killed by the GMO, hGM-CSF is expected to enhance the immune response to tumour antigens by stimulating specific immune cells in the immediate vicinity. This may also lead to a therapeutic effect on tumours located elsewhere in the body.

A single copy of the E. coli lacZ reporter gene has also been inserted within the viral TK gene.

This gene encodes a β-galactosidase enzyme which can be detected using a biochemical assay, allowing quick and easy detection of the GMO in blood and tissue samples collected from trial participants.

The GMO has not previously been trialled in Australia. However, it has been evaluated overseas in 13 completed and ongoing clinical trials, in countries that include the USA, Canada and South Korea. The proposed study would form part of an international multi-centre Phase 3 clinical trial.

Risk assessment

The risk assessment concludes that risks from the proposed dealings to the health and safety of people, or to the environment, are negligible to low. It is proposed that risk treatment measures be applied to manage the risks.

The risk assessment process considers how the genetic modification and proposed activities conducted with the GMOs could lead to harm to people or the environment. Plausible causal or exposure pathways are postulated that may give rise to harm for people or the environment from dealings with a GMO (risk scenarios) in the short and long term. This included consideration of the absence of the parent organism from the Australian environment and the potential for: expression of the introduced genes and genetic modifications to impact on the disease burden caused by the GM virus; infection of at-risk individuals; infection of animals; establishment of the GM virus in the environment; and gene transfer to other organisms.

A risk is only identified for further assessment when a risk scenario is considered to have some chance of causing harm. Pathways that do not lead to an adverse outcome, or could not reasonably occur, do not advance in the risk assessment process. Identified risks are characterised in relation to both the likelihood and seriousness of harm, taking into account information in the application (including proposed limits and controls), relevant previous approvals and current scientific/technical knowledge.

Risks to the health and safety of at-risk individuals from exposure, either through contact with trial participants who are shedding the GMO or contact with GMO-contaminated material which has been disposed of in general waste by trial participants, were estimated as negligible to low. Risk evaluation proposed that risk treatment should be applied to mitigate the low risks.

No other substantive risks were identified.

Important factors in reaching the conclusions of the risk assessment included: that the GM virus is expected to be attenuated relative to unmodified VACV; the introduced genes have not been associated with toxicity; unintended exposure would be minimised by precautions proposed by the applicant; and previous experience with the GMO in earlier clinical trials.

Summary iii


As risks to the health and safety of people, or the environment, from the proposed clinical trial of the GM virus have been assessed as negligible to low, the Regulator considers that the dealings involved do not pose a significant risk to either people or the environment.

Risk management plan

Risk management is used to protect the health and safety of people and to protect the environment by controlling or mitigating risk. The risk management plan evaluates options for treatment of identified risks, evaluates limits and controls proposed by the applicant, and considers general risk management measures. The risk management plan is given effect through licence conditions.

Treatment measures to mitigate the identified negligible to low risks to human health and safety were considered, and licence conditions proposed. These proposed conditions require patients participating in the trial to avoid contact with certain at-risk people following their initial treatment with the GMO until they have been assessed by their clinician, and that all contaminated waste generated during home care of GMO-related lesions is returned to the treating hospital for disposal via the clinical waste stream. These measures are considered sufficient to manage the identified negligible to low risks.

As this is a limited and controlled release, the draft licence also includes conditions that limit the scope and duration of the trial as well as controls in line with those proposed by the applicant, including administration of the GMO via intratumoural inoculation and by trained medical staff, exclusion of participants and staff at higher risk of adverse reactions and more likely to shed the GMO, educating trial participants about methods to minimise transmission of the GMO, appropriate containment and waste disposal provisions at the clinical site, destroying or exporting excess GMO that is not required for further studies, and transporting and storing the GMO in accordance with the Regulator’s Guidelines for the Transport, Storage and

Disposal of GMOs or other specific conditions.

The draft licence also contains a number of general conditions relating to ongoing licence holder suitability, auditing and monitoring, and reporting requirements, which include an obligation to report any unintended effects.

Summary iv


Call for comment

The Regulator invites submissions on the RARMP, including the draft licence conditions, for application DIR 140 from Clinical Network Services. The closing date for written submissions is 27 January 2016.

The Regulator would particularly value comments relating to risks to the health and safety of people or the environment that may be posed by the proposed clinical trial.

Note that as patient safety is addressed under the Therapeutic Goods Act 1989, the Regulator’s assessment focusses on risks posed to people other than those participating in the clinical trial, and to the environment.

All comments relating to the protection of people or the environment that are received by the closing date will be taken into account by the Regulator in finalising the RARMP, which will then inform the decision whether or not to issue a licence.

The consultation RARMP and other supporting documentation is available on the OGTR website under 'What's New'. You may also request a copy of the RARMP or the application from the OGTR - please quote application number DIR 140.

If you have any questions about the RARMP or the evaluation process, please contact:

The Office of the Gene Technology Regulator

MDP 54 GPO Box 9848 Canberra ACT 2601

Tel: 1800 181 030 Fax: 02 6271 4202 e-mail: ogtr@health.gov.au

OGTR Website: www.ogtr.gov.au

Summary v


Table of Contents

SUMMARY OF THE RISK ASSESSMENT AND RISK MANAGEMENT PLAN .................................... I

I NTRODUCTION ............................................................................................................................................................. I

T HE APPLICATION ........................................................................................................................................................ II

R ISK ASSESSMENT ....................................................................................................................................................... III

R ISK MANAGEMENT PLAN .......................................................................................................................................... IV

C ALL FOR COMMENT .................................................................................................................................................... V

TABLE OF CONTENTS ................................................................................................................................ VI

ABBREVIATIONS ....................................................................................................................................... VIII

CHAPTER 1 RISK ASSESSMENT CONTEXT ......................................................................................... 1

4.2

4.3

4.4

4.5

4.6

4.7

4.8

4.9

S ECTION 1 B ACKGROUND ......................................................................................................................................... 1

S ECTION 2 R EGULATORY FRAMEWORK .................................................................................................................. 1

2.1

Interface with other regulatory schemes .................................................................................................. 2

S ECTION 3 P ROPOSED D EALINGS ............................................................................................................................. 3

3.2

The proposed limits on the dealings (scope, scale, locations, duration and people) ............................... 8

3.3

The proposed controls to restrict the spread and persistence of the GM vaccine and its genetic material in the environment ..................................................................................................................... 8

S ECTION 4 T HE PARENT ORGANISM ......................................................................................................................... 9

4.1

Basic biology of Vaccinia Virus .............................................................................................................. 9

Host range and distribution ................................................................................................................... 10

VACV pathology................................................................................................................................... 11

VACV shedding from infected hosts .................................................................................................... 14

Host to host transmission ...................................................................................................................... 14

VACV persistence in infected hosts ...................................................................................................... 15

VACV-host interactions ........................................................................................................................ 15

Recombination with other poxviruses ................................................................................................... 15

Susceptibility of VACV to disinfectants ............................................................................................... 16

4.10

Survival of VACV in the environment .................................................................................................. 16

S ECTION 5 T HE GMO –

NATURE AND EFFECT OF THE GENETIC MODIFICATION ................................................. 16

5.1

5.2

Introduction to the GMO ....................................................................................................................... 16

The genetic modifications and their associated effects ......................................................................... 17

5.3

Characterisation of the GM virus .......................................................................................................... 21

S ECTION 6 T HE RECEIVING ENVIRONMENT ........................................................................................................... 26

6.1

6.2

Sites of release ....................................................................................................................................... 26

Relevant environmental factors ............................................................................................................. 26

6.3

6.4

6.5

Related viral species in the receiving environment ............................................................................... 27

Presence of the hGM-CSF gene and related genes in the environment ................................................. 27

Presence of the LacZ gene and related genes in the environment ......................................................... 27

S ECTION 7 R ELEVANT A USTRALIAN AND INTERNATIONAL APPROVALS .............................................................. 27

7.1

7.2

Australian approvals .............................................................................................................................. 27

International approvals .......................................................................................................................... 28

CHAPTER 2 RISK ASSESSMENT ........................................................................................................... 29

S ECTION 1 I NTRODUCTION ..................................................................................................................................... 29

S ECTION 2 R ISK I DENTIFICATION .......................................................................................................................... 30

2.1

2.2

Increased disease burden to the GM virus ............................................................................................. 36

Horizontal transfer of genes or genetic elements to other organisms .................................................... 43

S ECTION 3 R ISK CHARACTERISATION ................................................................................................................... 45

3.1

Risk Scenario 7 – exposure of at-risk individuals to GM virus shed by trial participants ..................... 45

3.2

Risk Scenario 8 – exposure of people or animals to GM virus following disposal of GM waste into landfill ............................................................................................................................................ 47

S ECTION 4 U NCERTAINTY ...................................................................................................................................... 49

S ECTION 5 R ISK E VALUATION ............................................................................................................................... 49

Table of Contents vi


CHAPTER 3 RISK MANAGEMENT ........................................................................................................ 51

S ECTION 1 B ACKGROUND ....................................................................................................................................... 51

S ECTION 2 R ISK TREATMENT MEASURES FOR SUBSTANTIVE RISKS EVALUATED AS REQUIRING

2.1

TREATMENT .......................................................................................................................................... 51

Summary of draft licence conditions proposed to manage identified risks ........................................... 52

S ECTION 3 G ENERAL RISK MANAGEMENT ............................................................................................................. 52

3.1

3.2

S ECTION 4 O THER RISK MANAGEMENT CONSIDERATIONS ................................................................................... 55

4.1

Consideration of the limits and controls proposed by Clinical Network Services Pty Ltd.................... 52

Summary of draft licence conditions proposed to limit and control the release .................................... 54

Applicant suitability .............................................................................................................................. 55

4.2

4.3

4.4

4.5

Contingency plans ................................................................................................................................. 55

Identification of the persons or classes of persons covered by the licence ............................................ 55

Reporting requirements ......................................................................................................................... 56

Monitoring for Compliance ................................................................................................................... 56

S ECTION 5 C ONCLUSIONS OF THE CONSULTATION RARMP ................................................................................ 56

CHAPTER 4 PROPOSED LICENCE CONDITIONS ............................................................................. 57

I NTERPRETATIONS AND D EFINITIONS ........................................................................................................................... 57

G ENERAL CONDITIONS AND OBLIGATIONS ................................................................................................................... 59

Obligations of the Licence Holder ........................................................................................................................... 59

Provision of new information to the Regulator........................................................................................................ 61

Obligations of persons covered by the licence ........................................................................................................ 62

L IMITS AND CONTROL MEASURES ................................................................................................................................. 62

Limits on the release ................................................................................................................................................ 62

Controls on the Release ........................................................................................................................................... 63

A DDITIONAL R EPORTING R EQUIREMENTS .................................................................................................................... 66

Notice of commencement and completion of the trial ............................................................................................. 66

Annual Report ......................................................................................................................................................... 67

Testing methodology ............................................................................................................................................... 67

REFERENCES ................................................................................................................................................ 68

Table of Contents vii


IC

50 mL

μg

OGTR pfu

PPE

RARMP

TGA the Act

IV

FSANZ

GM

GM-CSF

GMO

GTTAC hGM-CSF

HGT the Regulations the Regulator

TK

US CDC

USA

VACV

VIG

WHO

Abbreviations

ACIP

APVMA

ARTG

BSC

CCI

CRO

DIR

DNA

DNIR

IATA

ICH-GCP

Advisory Committee on Immunization Practices

Australian Pesticides and Veterinary Medicines Authority

Australian Register of Therapeutic Goods biological safety cabinet

Confidential Commercial Information under section 185 of the Gene Technology Act 2000

Clinical research organisation (in this case PPD Australia Pty Ltd)

Dealings involving Intentional Release

Deoxyribonucleic acid

Dealings not involving Intentional Release

International Air Transport Association

Guidelines for Good Clinical Practice of the International Council for Harmonisation of Technical

Requirements for Registration of Pharmaceuticals for Human Use intravenous

Food Standards Australia New Zealand

Genetically modified

Granulocyte-macrophage colony-stimulating factor

Genetically modified organism

Gene Technology Technical Advisory Committee human Granulocyte-Macrophage Colony-Stimulating Factor

Horizontal gene transfer half maximal inhibitory concentration millilitre microgram

Office of the Gene Technology Regulator plaque-forming units

Personal Protective Equipment

Risk Assessment and Risk Management Plan

Therapeutic Goods Administration

The Gene Technology Act 2000

The Gene Technology Regulations 2001, as amended 2011

The Gene Technology Regulator thymidine kinase

United States Center for Disease Control

United States of America

Vaccinia virus

Vaccinia Immunoglobulin

World Health Organisation

Abbreviations viii


Chapter 1 Risk assessment context

Section 1 Background

1.

An application has been made under the Gene Technology Act 2000 (the Act) for

Dealings involving the Intentional Release (DIR) of genetically modified organisms (GMOs) into the Australian environment.

2.

The Act in conjunction with the Gene Technology Regulations 2001 (the Regulations), an inter-governmental agreement and corresponding legislation that is being enacted in each

State and Territory, comprise Australia’s national regulatory system for gene technology. Its objective is to protect the health and safety of people, and to protect the environment, by identifying risks posed by or as a result of gene technology, and by managing those risks through regulating certain dealings with GMOs.

3.

This chapter describes the parameters within which potential risks to the health and safety of people or the environment posed by the proposed release are assessed. The risk assessment context is established within the regulatory framework and considers application-

specific parameters (Figure 1).

RISK ASSESSMENT CONTEXT

LEGISLATIVE REQUIREMENTS

(including Gene Technology Act and Regulations)

RISK ANALYSIS FRAMEWORK

OGTR OPERATIONAL POLICIES AND GUIDELINES

PROPOSED DEALINGS

Proposed activities involving the GMO

Proposed limits of the release

Proposed control measures

PARENT ORGANISM

Origin and taxonomy

Biological characterisation

GMO

Introduced or deleted genes (genotype)

Novel traits (phenotype)

RECEIVING ENVIRONMENT

Environmental conditions

Presence of related species

Presence of similar genes

PREVIOUS RELEASES

Figure 1.

Summary of parameters used to establish the risk assessment context

Section 2 Regulatory framework

4.

Sections 50, 50A and 51 of the Act outline the matters which the Gene Technology

Regulator (the Regulator) must take into account, and consultation that is required when preparing the Risk Assessment and Risk Management Plans (RARMPs) that form the basis of decisions on licence applications. In addition, the Regulations outline matters the Regulator must consider when preparing a RARMP.

5.

In accordance with section 50A of the Act, this application is considered to be a limited and controlled release application, as its principal purpose is to enable the applicant to conduct experiments and the applicant has proposed limits on the size, locations and duration of the release, as well as controls to restrict the spread and persistence of the GMOs and their genetic material in the environment. Therefore, the Gene Technology Regulator (the Regulator) was not required to consult with prescribed experts, agencies and authorities before preparation of the RARMP (see section 50 of the Act).

Chapter 1 – Risk assessment context 1


6.

Section 51 of the Act and regulation 9A of the Regulations outline the matters the

Regulator must take into account in preparing a RARMP.

7.

Section 52 of the Act requires the Regulator to seek comment on the RARMP from the

States and Territories, the Gene Technology Technical Advisory Committee, Commonwealth authorities or agencies prescribed in the Regulations, the Minister for the Environment, relevant local council(s), and the public.

8.

The Risk Analysis Framework explains the Regulator’s approach to the preparation of

RARMPs in accordance with the legislative requirements (OGTR 2013). Additionally, there are a number of operational policies and guidelines developed by the Office of the Gene

Technology Regulator (OGTR) that are relevant to DIR licences. These documents are available from the OGTR website.

2.1 Interface with other regulatory schemes

9.

Gene technology legislation operates in conjunction with other regulatory schemes in

Australia. Any dealings conducted under a licence issued by the Regulator may also be subject to regulation by other Australian government agencies that regulate GMOs or genetically modified (GM) products, including Food Standards Australia New Zealand (FSANZ), the

Australian Pesticides and Veterinary Medicines Authority (APVMA), the Therapeutic Goods

Administration, the National Industrial Chemicals Notification and Assessment Scheme and the Department of Agriculture. These dealings may also be subject to the operation of State legislation declaring areas to be GM, GM free, or both, for marketing purposes.

10.

Medicines and other therapeutic goods for use in Australia are required to be assessed for quality, safety and efficacy under the Therapeutic Goods Act 1989 and must be included in the

Australian Register of Therapeutic Goods (ARTG). The Therapeutic Goods Administration

(TGA) is responsible for administering the provisions of this legislation. Clinical trials of therapeutic products that are experimental and under development, prior to a full evaluation and assessment, are also regulated by the TGA through the Clinical Trial Exemption (CTX) scheme or the Clinical Trial Notification (CTN) scheme.

11.

For clinical trials, TGA has regulatory responsibility for the supply of unapproved therapeutic products. In terms of risk to individuals participating in a clinical trial, TGA (as the regulator), the trial sponsor, the investigators and the Human Research Ethics Committee

(HREC) at each trial site all have roles in ensuring participants’ safety under the

Therapeutic

Goods Act 1989 . However, where the trial involves a GMO, authorisation is also required under gene technology legislation. To avoid duplication of regulatory oversight, and as risks to trial participants are addressed through the above mechanisms, the Regulator’s focus is on assessing risks posed to people other than those participating in the clinical trial, and to the environment. This includes risks to people preparing and administering the GM virus, and risks associated with import, transport and disposal of the GMO.

12.

The International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Guidelines for Good Clinical Practice (ICH-GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. The guideline was developed with consideration of the current good clinical practices of the European Union, Japan, and the

United States, as well as those of Australia, Canada, the Nordic countries and the World Health

Organization (WHO). TGA has adopted the ICH-GCP in principle as Note for Guidance on

Good Clinical Practice (designated CPMP/ICH/135/95), which provides overarching guidance for conducting clinical trials in Australia which fall under TGA regulation.

13.

The National Health and Medical Research Council (NHMRC) has issued the National

Statement on the Ethical Conduct in Research Involving Humans (National Health and Medical

Research Council 2013). This document sets the Australian standard against which all research


Office of the Gene Technology Regulator involving humans is reviewed. The Therapeutic Goods Act 1989 requires that the use of a therapeutic good in a clinical trial must be in accordance with the ethical standards set out in this document.

14.

Approval by a HREC is also a fundamental requirement of a clinical trial. HRECs conduct both ethical and scientific assessment of the proposal and in addition often consider issues of research governance. Other elements of governance of clinical trials that are considered by HRECs include appropriate informed consent, specific inclusion and exclusion criteria, data monitoring and vaccine accounting and reconciliation.

15.

The Department of Agriculture administers Australian biosecurity conditions for the importation of biological products under the Quarantine Act 1908 . Biological products include animal or microbial derived products such as foods, therapeutics, laboratory materials and vaccines (including GM vaccines). Import of the GM virus is subject to regulation by the

Department of Agriculture and the Regulator.

Section 3 Proposed Dealings

16.

CNS has proposed a clinical trial of a genetically modified (GM) live virus (JX-594; also known as Pexa-Vec). The GM virus is being developed as a treatment for solid tumours of various origin and has been tested in patients with metastatic melanoma, and liver, renal and colorectal cancers. In the proposed trial, the GMO will be tested for efficacy against advanced hepatocellular carcinoma (HCC), a common type of liver cancer. It will be administered to cancer patients by direct injection into solid tumours located in the liver.

3.1 The proposed clinical trial

3.1.1 Details of the clinical trial

17.

The purpose of the trial is to assess the efficacy and safety of the GM virus when provided in conjunction with a standard treatment for HCC (the chemotherapy drug sorafenib), compared with the standard treatment alone.

18.

The proposed study is part of an international multi-centre Phase 3 clinical trial. A total of 600 patients globally are to take part in the study, which will be conducted at approximately

120 sites worldwide, including in North America, Asia and Europe.

19.

The international trial sponsor is SillaJen, Inc., based in The Republic of Korea. SillaJen

Inc. has contracted Clinical Network Services Pty Ltd (CNS) to manage regulatory compliance for the Australian component of the trial, and PPD Australia Pty Ltd (PPD) to act as the

Clinical Research Organisation (CRO) and liaise with individual study sites. CNS will audit trial sites periodically and ensure compliance with regulatory requirements.

20.

The Australian component of the trial will involve 40-50 adult volunteers at approximately 10-15 study sites. The applicant plans to conduct the trial in hospitals that provide specialised cancer-treatment services and access to patients with liver cancer.

21.

The trial will be divided into three stages:

1) Screening: medical history and tumour status of prospective volunteers will be examined and their suitability to participate in the study assessed.

2) Treatment: participants will undergo a series of three treatments over a four week period. At each treatment, a total dose of 1x10

9

plaque-forming units (pfu) of the

GM virus will be injected into one or more liver tumours. Patients will be observed for at least eight hours after each treatment before being released from the hospital.

At subsequent visits, participants will be asked to report any adverse reactions experienced since the onset of treatment. Before the second and third treatments,


Office of the Gene Technology Regulator specimens (e.g. blood samples) will be collected for laboratory analysis. These will be exported for analysis overseas, but may if required be analysed in Australia.

3) Follow-up and monitoring: conventional therapy will commence two weeks after the final treatment with the GMO and participants will thereafter be assessed at 3-week intervals. At each visit, blood samples will be collected for laboratory analysis and any adverse reactions reported.

22.

Under the Gene Technology Act 2000 , the proposed clinical trial involves the following dealings: a) importing the GMO; b) conducting experiments with the GMO; c) transporting the GMO; d) disposing of the GMO; and e) possession (including storage) and use of the GMO for the purpose of any of the above activities.

3.1.2 Selection of trial participants

23.

Relevant inclusion criteria to be used by study site investigators include: a) adults of any gender.

24.

Relevant exclusion criteria include: a) pregnant women; b) persons with known significant immunodeficiency due to underlying illness (e.g.

HIV/AIDS) and/or high dose immunosuppressive medication; c) persons with an ongoing and severe inflammatory skin condition requiring medical treatment; d) persons with a history of severe eczema requiring prior medical treatment; e) persons who have previously experienced a severe systemic reaction or side effect due to previous vaccination with VACV; and f) persons unable or unwilling to comply with the requirements of the trial protocol.

25.

For the purpose of this document, individuals meeting the criteria listed in paragraph 24

(a) – (e) will be referred to as ‘Excluded Individuals’.

3.1.3 Instructions to trial participants

26.

Trial participants treated with the GMO will receive instructions intended to minimise interpersonal spread of the GM virus – in particular, to individuals at risk of developing severe

disease (i.e. ‘Excluded Individuals’ (paragraph 25)). The applicant has confirmed that these

behaviours are a required part of the clinical trial protocol, and unwillingness or inability to

comply is grounds for exclusion from the trial (see paragraph 24 (f)).

27.

For all trial participants, these include: a) frequent hand washing with soap or hand disinfectant containing at least 60% alcohol; b) respiratory hygiene and cough etiquette followed for two weeks after initial treatment; and c) refraining from blood, tissue or organ donation while taking study medications.

28.

Patients who develop GMO-related pustules will also be expected to:


Office of the Gene Technology Regulator a) cover skin pustules with a non-occlusive dressing (e.g. gauze); b) where mouth pustules are present, wear a mask and avoid sharing items such as toothbrushes and eating utensils; c) avoid, and ensure others avoid, direct physical contact with pustules or any potentially contaminated material unless necessary for patient care. When caring for the pustule, disposable gloves should be worn and hands washed or disinfected afterwards; d) prevent self-inoculation by avoiding touching other body parts (e.g. eyes, nose) after direct contact with the pustule or with potentially contaminated material; and e) avoid direct physical contact with children under 12 months of age and ‘Excluded

Individuals’ (paragraph 25) until the pustules have healed.

3.1.4 Transport and storage of the GMO

29.

The GMO will be manufactured according to Good Manufacturing Practice (GMP) guidelines in France and imported into Australia. Concentrated virus will be supplied in small volumes in sealed pharmaceutical-quality vials.

30.

Vials will be labelled to indicate the contents, quantity and clinical trial details. Shipping cartons will be labelled to indicate that they contain GMOs and with the applicant’s contact information, in accordance with the Regulator’s

Guidelines for the Transport, Storage and

Disposal of GMOs .

31.

For transport during import and distribution within Australia, primary containers will be sealed within leak-proof secondary packaging and further packed to meet the requirements of

International Air Transport Association (IATA) shipping classification Biological Substance,

Category B, UN 3373. These satisfy the containment requirements outlined in the Regulator’s

Guidelines for the Transport, Storage and Disposal of GMOs .

32.

Packages will be transported by commercial courier companies experienced in the transport of pharmaceutical products, and in accordance with IATA Dangerous Goods

Regulations and, within Australia, the Australian Dangerous Goods Code (edition 7.3).

33.

The GMO will be held at a central storage facility in Australia (Flinders Clinical Trial

Services, Adelaide SA) and distributed to study sites as needed. Individual sites will typically hold small quantities of the GMO at any one time, stored in a secure location with access restricted to staff in the dispensing pharmacy or laboratory, and otherwise in accordance with the Regulator’s


34.

For all transport within the clinical site, the GM virus will be sealed within a primary container (e.g. vial, capped syringe or intravenous (IV) infusion bag) and placed within a leakproof secondary container or bag clearly marked with a biohazard symbol.

35.

Blood and tissue samples collected from trial participants during the study will be exported for analysis overseas. These samples may contain the GMO, and will be transported in accordance with the Regulator’s Guidelines for the Transport, Storage and Disposal of

GMOs .

3.1.5 Handling of the GMO

36.

Hospital staff conducting the dealings will be trained in product handling by a representative of SillaJen, Inc. and in specific GMO-related requirements by a CNS representative.

Procedures

37.

The GM virus will be dispensed within a hospital pharmacy or laboratory by staff designated and trained for this study, and only with written authorisation from the lead


Office of the Gene Technology Regulator investigator at the site. The international trial sponsor will provide guidance on product handling, safety precautions and decontamination procedures.

38.

Concentrated GM virus will be drawn into a syringe, diluted with saline solution in a mixing container then drawn into one or more dosing syringes according to the number of tumours to be injected. The procedure will require the use of sharps and, depending on local procedures, could involve removal of contaminated needles from filled syringes. Syringes will be capped and transported to the clinic for administration to the patient.

39.

Appropriately qualified medical staff will administer the GMO by image-guided intratumoural injection. The needle will be fully inserted into each tumour before the syringe containing the GM virus is attached to the injection apparatus via flexible tubing. Before withdrawing the needle, the apparatus will be flushed with saline solution to reduce GMO leakage from the injection site.

Safety considerations

40.

Clinical trial documents

2

prepared by the international trial sponsor outline specific precautions to be taken by clinical staff involved in the trial.

41.

Hospital staff who meet the criteria listed in paragraph 24 (a) – (e) will be excluded from

directly handling the GMO, administering it to patients, and caring for patients who present with GMO-related pustules.

42.

When handling the GMO, personal protective equipment (PPE) including gown, gloves, eye protection and a surgical mask must be worn. In addition, relevant institutional policies and procedures should be followed. Vaccination of staff with VACV is not required.

43.

Additional requirements while dispensing concentrated GMO include the use of a

Class II biological safety cabinet (BSC) and PC2 work practices.

44.

Administration of the GMO and subsequent care of inoculated patients will be, at a minimum, in accordance with Universal Standard Precautions (World Health Organisation

2007a) and the Australian Guidelines for the Prevention and Control of Infection in Healthcare

(National Health and Medical Research Council 2010). These aim to reduce transmission of infectious organisms from both recognized and unrecognized sources in the clinical setting.

Appropriate practices include (but are not limited to) hand hygiene, use of PPE as appropriate and based on risk assessment, safe sharps handling and disposal practices, safe handling of potentially contaminated equipment or surfaces in the patient environment, respiratory hygiene/cough etiquette and correct cleaning and waste management.

45.

Where returning patients present with GMO-related lesions, from which the GM virus may be shed, study sites are advised to implement additional ‘Contact Precautions’ based on local risk assessment. Examples include additional PPE, dedicated bedside diagnostic devices and use of single patient rooms. Where single rooms are unavailable, patients could be placed

in rooms with patients who are not Excluded Individuals (paragraph 25).

2 Clinical trial documents provided as part of the application include the Study Protocol,

Investigator’s Brochure,

Pexa-Vec Guidelines, Pexa-Vec Guidelines for Pharmacy Staff and Pexa-Vec Guidelines for Clinical Staff

With the exception of Pexa-Vec Guidelines for Clinical Staff, these documents are under consideration as

Confidential Commercial Information (CCI) under section 185 of the Act. Any confidential information will be made available to the prescribed experts and agencies.



3.1.6 Disposal of the GMO (including waste contaminated with the GMO)

46.

Disposable materials contaminated with the GM virus (e.g. syringes, catheters, needles, tubing, gloves, vials, bandages etc) will be discarded into appropriate biomedical waste containers and disposed of following standard institutional procedures for infectious clinical waste and in accordance with applicable State and Territory legislation. This may include rendering the waste inert by steam sterilisation, high temperature incineration or chemical treatment, and may take place at the medical facility or involve the use of registered waste contractors. Waste generated at clinical sites will not be left unattended in a public area.

47.

After handling the GMO, work surfaces will be decontaminated with an appropriate chemical disinfectant, following standard institutional procedures. Contaminated textiles (e.g. linens, towels and clothing) will be laundered using routine protocols for healthcare facilities

(e.g. hot (71°C) water with detergent and hot air drying).

48.

When changing dressings at home, patients will be instructed to place soiled dressings and other contaminated items in a sealed container or zip-loc plastic bag and dispose of it with general household waste. Contaminated textiles should be laundered in hot water with detergent or treated with dilute bleach.

49.

Any unused GM virus will be destroyed locally, according to written instructions provided by the international sponsor, or returned to a nominated central facility. This facility will either destroy the GMO or coordinate its return to the international sponsor.

3.1.7 Contingency plans

50.

In the event of accidental human exposure to the GMO, the applicant has proposed the following: a) implement institutional guidelines, such as documented in the Australian Guidelines for the Prevention and Control of Infection in Healthcare ; b) wash the area thoroughly with soap and water; c) cover affected area with a non-occlusive dressing until complete resolution; and d) report the incident to the study investigator and trial sponsor.

51.

In the event of a clinically-significant reaction that may be related to the GMO, the study investigator should immediately contact the trial sponsor and seek appropriate infectious disease expertise.

52.

Medications recommended for treating some adverse reactions to VACV infection (see

Section 4.3.4) are available in Australia and from the international trial sponsor. Country-

specific treatment protocols will be provided to clinical sites. The applicant has stated that at least one course of Vaccinia Immunoglobulin (VIG) treatment is available in Australia. A stockpile sufficient for three patients will be maintained in Singapore and can be transported to study sites in Australia within 24 hours. The anti-viral drug Cidofovir is available within

Australia and is suggested as an off-label second line of treatment (see paragraph 88).

3.1.8 Record keeping

53.

Each site will maintain records of all GMO received, dispensed and destroyed. These records will be verified by the CRO and licence holder during regular site visits.

54.

On completion of the study at each trial site, the sponsor and licence holder will verify that all used vials have been decontaminated and disposed of, all unused GMO has been returned to the international sponsor or destroyed, and no GMO remains at the site.



3.2 The proposed limits on the dealings (scope, scale, locations, duration and people)

55.

The trial would take place in hospitals throughout Australia. While clinical sites have not been finalised, participating hospitals are likely to be located in Brisbane, Sydney, Melbourne,

Adelaide, Perth and Fremantle. The study will run from the date of issue of the licence until after the required number of participants have been enrolled, treated and any follow-up studies undertaken. The applicant intends to enrol a maximum of 50 patients in the Australian component of the trial.

3.3 The proposed controls to restrict the spread and persistence of the GM vaccine and its genetic material in the environment

56.

The applicant has proposed a number of controls to limit exposure to the GM virus, and to restrict its spread and persistence in the environment. These include:

 excluding prospective participants at higher risk of severe reaction to VACV, which is characterised by extensive pustule formation and increased opportunity for viral shedding into the environment;

 excluding staff who are at higher risk of severe reaction to VACV from handling the

GMO and caring for patients presenting with GMO-related pustules;

 administering the GM virus via intratumoural injection, which is associated with reduced viral shedding compared with intravenous infusion;

 requiring that the GMO be administered by appropriately trained medical staff in a hospital setting and in accordance with WHO Standard Universal Precautions and ICH-

GCP;

 requiring that staff handling the GMO and caring for patients presenting with pustules wear and use appropriate protective clothing and equipment;

 requiring trial participants to take precautions intended to minimise interpersonal spread of the GMO;

 requiring that trial participants who develop GMO-related pustules avoid direct physical contact with individuals at risk of severe reaction to VACV infection;

 ensuring contingency plans are in place to manage any exposure to the GM virus and treat any severe vaccinia-related illness that may eventuate;

 transporting and storing the GM virus generally in accordance with relevant guidelines and regulations 3 ;

 disposing of waste generated at the clinical trial site in accordance with standard clinical waste disposal practices as required by the relevant local and state legislation, and instructing trial participants to place contaminated waste generated at home in a sealed primary container before disposal; and

 destroying or returning unused GMO on completion of the study, and maintaining records at each clinical site of all GMO received, dispensed and destroyed.

57.

The suitability of these controls and the limits outlined above is assessed in Chapter 3.

3

The Regulator’s Guidelines for the Transport, Storage and Disposal of Genetically Modified

Organisms , or IATA Transportation Regulations



Section 4 The parent organism

58.

Vaccinia virus (VACV) is a member of the Orthopoxvirus genus of the family

Poxviridae , subfamily Chordopoxvirinae . This genus also includes the human pathogen

Variola virus (causative agent of smallpox), as well as Monkeypox virus (monkeypox) ,

Cowpox virus (cowpox) , Horsepox virus (horsepox) , Ectromelia virus (mousepox) and others.

It should be noted that the human disease known as chickenpox is caused by the Varicella zoster virus, which is not a member of family Poxviridae .

59.

There is extensive clinical experience with VACV as it was used globally as a vaccine against smallpox prior to the latter’s declared eradication in 1980 (Jacobs, 2009). VACV is not known to exist naturally in the environment. Its origin is unknown, and it may have evolved from other related poxviruses at some point during 150 years of propagation and use as a vaccine. It is genetically distinct from both cowpox virus and variola virus, and most closely related to horse pox virus (Jacobs et al. 2009).

60.

Due to their evolution in different parts of the world over 150 years of smallpox vaccination, many strains of VACV exist (e.g. Paris, Copenhagen, Bern, Ankara, Lister and

New York City Board of Health (NYCBH) strains). These differ in viral characteristics, host range, pathogenicity and prevalence of adverse reactions to vaccination. Overall, vaccination with the NYCBH strain caused the lowest rate of adverse reactions (Jacobs et al. 2009;

Kretzschmar et al. 2006; Osborne et al. 2007; Shen & Nemunaitis 2005).

61.

JX-594, the GMO that is the subject of the proposed clinical trial, is derived from the

Dryvax TM smallpox vaccine (Wyeth Laboratories), also known as ‘Wyeth’ strain. Dryvax TM was prepared from the NYCBH VACV strain and contains a highly heterogeneous population of closely related viruses with varying pathogenicity. Its phenotype is therefore the aggregate consequence of infection with this diverse collection (Nalca & Zumbrun 2010; Osborne et al.

2007). JX-594 was isolated by plaque purification after the recombination event that created the GMO (see Section 5). Therefore, it is clonally pure but not entirely characterised.

4.1 Basic biology of Vaccinia Virus

62.

The lifecycle of a virus involves transmission of infective virus particles to a new host organism, attachment and entry into susceptible host cells, replication of the viral genome, production of viral proteins, assembly of new virus particles and, finally, release of progeny virus particles – often accompanied by cell lysis. Viruses have co-evolved with their host species and are often specific for a narrow range of host organisms and infect only certain cell types within those hosts.

63.

Like other poxviruses, VACV is a large enveloped virus with a linear double-stranded

DNA genome, approximately 192 kilo bases (kb) in length. The genome encodes around 200 proteins with roles in viral entry, transcription of viral genes, DNA synthesis, assembly of virus particles, and suppression of the host anti-viral response (Liu et al. 2014).

64.

VACV is a non-integrating virus, meaning it does not integrate into the genome of cells it infects, and its entire life cycle takes place within the cytoplasm of host cells. This means

VACV cannot utilise host enzymes for DNA replication and gene transcription, as these reside in the cell nucleus. It must therefore encode its own.

65.

VACV genes are expressed in three highly coordinated temporal waves: early, intermediate and late, with each wave controlled by a specific set of transcription factors. The viral core contains the entire machinery needed to commence transcription of early genes, while expression of intermediate and late genes relies on transcription factors synthesised during the early and intermediate phases, respectively. A fourth group of genes (termed earlylate) are expressed constitutively. The promoters for each group of genes have distinctive


Office of the Gene Technology Regulator sequence elements recognized by specific viral proteins, providing the basis for a programmed cascade of gene regulation (Baur et al. 2010; Lefkowitz et al. 2006; Shen & Nemunaitis 2005).

66.

Replication of viral DNA yields 10 000 copies per cell within hours of infection. In the final stages of the VACV lifecycle, new virions assemble and acquire one or more outer membranes to form one of three distinct types of infectious particle. The entire lifecycle of

VACV is usually complete with 24 hours and ends with lysis of the infected cell and the release of as many as 10 000 virus particles (Lefkowitz et al. 2006; Shen & Nemunaitis 2005;

Thorne et al. 2005).

4.2 Host range and distribution

67.

VACV is considered a laboratory virus with no known natural host or reservoir, but can infect a wide range of mammals. These include humans, several monkey species, a variety of rodents, rabbits, cattle, buffalo, sheep, horses, and domestic cats and dogs (Abrahao et al. 2010;

Adams et al. 2007; Artois et al. 1990; Bennett et al. 1989; Brochier et al. 1989; Dumbell &

Richardson 1993; Felipetto et al. 2012; Oliveira et al. 2015; Robinson & Mercer 1988; Riyesh et al. 2014).

68.

VACV is capable of causing disease symptoms in human, mice, rabbits, cattle, horses and buffalo. The related cowpox virus infects and causes disease symptoms and viraemia in domestic cats – in fact, cats are the most frequently recognised host of cowpox virus in Great

Britain. Dermal pock formation due to VACV (Lister strain) has been demonstrated in cats, however the infectious dose was higher than that of cowpox virus (Bennett et al. 1989).

69.

Vaccinia can infect and replicate to some degree in canines, including domestic dogs, as genetically modified VACVs are effective therapeutics in these species (Autio et al. 2014;

Rupprecht et al. 2005). It is not clear whether unmodified VACV can cause disease in dogs.

70.

Birds are not known as a target for VACV, but a study of a GM VACV-based rabies vaccine (Section 5.2.1) demonstrated sufficient viral replication in several Canadian bird species to permit seroconversion (Artois et al. 1990).

71.

Although used extensively in the past as a smallpox vaccine, persistence of VACV in the environment has been limited. Naturally-occurring infections with VACV or close relatives have been documented only in India and Brazil.

72.

Buffalopox virus , which appears to have become established in India, is considered a variant of VACV (Baxby 1996; Condit 2010; Moussatche et al. 2008).

73.

VACV appears to have become endemic in Brazil. Outbreaks of zoonotic disease caused by VACV-like viruses and affecting dairy cattle and rural workers have occurred since 1999, and significant levels of VACV infection have been found in remote Amazonian wildlife

(Abrahao et al. 2009; Abrahao et al. 2010; Condit 2010; Oliveira et al. 2015). The origin of these viruses is unclear, but they appear genetically distinct from the VACV vaccine strains used during the post-1966 smallpox eradication campaign. Their origins may lie with earlier

VACV imports beginning in the early 1800s, however strains indigenous to South America have not been ruled out (Drumond et al. 2008; Trindade et al. 2007).

74.

Vaccinia virus (VACV) now causes an occupational disease in Brazil that is primarily associated with the handling of infected dairy cattle (Abrahao et al. 2015; Costa et al. 2015;

World Health Organisation 2007a). Infection in humans is characterised by pustular skin lesions, mainly on the hands, accompanied by systemic symptoms such as fever, myalgia, headache and lymphadenopathy (de Assis et al. 2013; Kroon et al. 2011). Disease can be severe, with 12 out of 26 infected rural workers hospitalised in an outbreak in 2010 (Abrahao et al. 2015).



4.3 VACV pathology

4.3.1 Normal reactions to smallpox vaccination

75.

In humans, pathology related to VACV is best understood in the context of smallpox vaccination. VACV is generally administered by scarification, i.e. by scratching the skin with a two-pronged needle dipped in virus solution. The vaccinee normally develops a single lesion at the site of exposure around 3-4 days post-vaccination. Over 2-3 weeks, the lesion progresses through the following stages, typical of orthopoxviral lesions: macule, papule, vesicle, pustule and crusted scab (Figure 1). This is often accompanied by flu-like symptoms (fever, malaise, headache, nausea and muscle aches), swelling and redness around the vaccination site, swelling and tenderness of the draining lymph node, and less commonly, an urticarial-like rash. These reactions resolve spontaneously and require only observation and symptomatic treatment.

Historically, about 21% of first time vaccinees were sufficiently concerned about their symptoms to seek medical attention (Cono et al. 2003; Fulginiti et al. 2003; Maurer et al.

2003).

Figure 2.

Natural progression of response to smallpox vaccine: papule (day 4), vesicle (day 7), pustule (day 14) and scab (day 21) (from (Maurer et al.

2003)).

4.3.2 Pathogenesis of poxvirus infection

76.

Natural infection with most of the pathogenic poxviruses occurs through the respiratory

tract, although VACV appears to be an exception (see paragraph 95). Infection is also caused

by inoculation into the skin or contact with broken skin, and possibly through mucosal membranes. The virus replicates at the site of inoculation and causes dermal hyperplasia and leukocyte infiltration (Baxby 1996). Orthopoxviruses display a tropism for epithelial cells and

tend to produce cutaneous lesions as described above (Section 4.3.1) (Moussatche et al. 2008).

4.3.3 Adverse reactions to smallpox vaccination

77.

Although smallpox vaccination was generally safe and effective, it is well-documented that it caused serious adverse reactions at a higher rate than any other type of vaccine. Most complications occurred in the vaccinated individuals, but as VACV is transmissible, serious and even fatal reactions sometimes developed in others. Several types of adverse event occurred in healthy people, while others were associated with specific risk factors (Cono et al.

2003; Fulginiti et al. 2003; Lane & Goldstein 2003a; Lane & Goldstein 2003b; Maurer et al.

2003; Neff et al. 2002; Wittek 2006).

78.

Accidental implantation (or self-inoculation) of a body part other than the vaccination site is the most common complication, with the face, eyelid, nose, lips, genitalia and anus most often affected. Transmission to another non-immune person can also occur by this route. The best preventative measure as recommended by the US Center for Disease Control (CDC)

Advisory Committee on Immunization Practices (ACIP) is consistent hand hygiene using antimicrobial soap and water, or alcohol-based hand disinfectant, after contact with the vaccination site or with materials that have come into contact with it (Maurer et al. 2003; Wharton et al.



2003). No specific treatment is needed if there are only a few implanted lesions. However, multiple or confluent lesions warrant treatment with vaccinia immunoglobulin (VIG).

79.

About 6% of patients with vaccinia in the eye develop vaccinial keratitis . This may occur where there is injury to the cornea or conjunctiva, allowing viral replication. Ulceration and scarring as the lesion heals can lead to permanent impairment of vision (Fulginiti et al. 2003).

80.

Generalised vaccinia is a rare condition associated with viraemic spread of virus from the vaccination site in presumably healthy individuals. Systemic infection enables skin lesions to form in locations distant from the vaccination site and sometimes covering the entire body.

Onset is typically within a week of vaccination and, while visually distressing, the condition usually resolves in 1-2 weeks. Extensive or recurrent disease is treatable with VIG.

81.

Post-vaccinial central nervous system (CNS) disease – post-vaccinial encephalopathy most often affected children under age two and developed 6-10 days after vaccination, while postvaccinial encephalitis usually affected those older than two years and developed 11-15 days post-vaccination. The conditions were characterised by headache, fever, vomiting, seizures and coma and up to one third of cases were fatal. In addition, up to half of the survivors had permanent neuralgic problems.

82.

Congenital or fetal vaccinia was a rare complication, with only 50 cases reported in the literature (Cono, 2003). It results from maternal exposure to VACV during pregnancy or shortly before conception and often led to stillbirth or neonatal death. Due to its rarity, specific risk factors have not been determined. No other specific risks to fetuses or pregnant women have been identified.

83.

Progressive vaccinia (or vaccinia necrosum ) is life-threatening and the most severe complication of smallpox vaccination. It is defined as a spreading necrosis at the site of inoculation, with or without metastatic necrotic lesions occurring elsewhere on the body (Neff,

2002). It occurred only in immune-compromised individuals whose defective immunity left them unable to resolve the infection. The condition involves unchecked viral replication, with slow but progressive necrosis leading to severe viraemia, shock and death.

84.

Eczema vaccinatum (EV) is a localized or generalized pustular rash which can occur anywhere on the body but displays a preference for areas of previous atopic dermatitis lesions as the disrupted skin allows viral implantation. People with a history of atopic dermatitis are at greatest risk of this complication, and more reported cases were due to contact transmission than to primary vaccination. EV lesions follow a similar course to the normal vaccination lesion but confluent lesions may occur. Fever and lymph node involvement are common and patients are systemically ill. Without treatment, the condition can be fatal.

85.

A number of retrospective studies have estimated the frequency of these complications.

Findings vary and are limited by the accuracy of reporting, variation in definitions used at the time, and availability of clinical data. Aggregate data from four studies of US data are shown in

Table 1. It is generally acknowledged that populations today include more immunosuppressed people, more people with no immunity to VACV, and higher rates of atopic dermatitis than when VACV was widely used for smallpox vaccination (Cono et al. 2003; Engler et al. 2002;

Fulginiti et al. 2003). However, medical interventions are also more advanced.



Table 1

Estimated rates of occurrence of adverse events associated with smallpox (vaccinia virus)

vaccination. From (Fulginiti et al. 2003).

4.3.4 Treatment of adverse reactions

86.

Vaccinia immunoglobulin (VIG) is made from the plasma of recently vaccinated people and has been successfully used to treat certain complications of vaccinia infection. It is recommended for treating severe cases of accidental implantation, severe generalised vaccinia, eczema vaccinatum and severe progressive vaccinia. It is not recommended for mild instances of accidental implantation, mild or limited generalised vaccinia, and post-vaccinial CNS disease. VIG is contraindicated in patients with vaccinia keratitis (Centers for Disease Control and Prevention 2003; Cono et al. 2003; Enserink 2002; Maurer et al. 2003).

87.

VIG has not been tested in controlled clinical trials. It is available from the US CDC in limited quantity and under an Investigational New Drug (IND) protocol for treatment of specific smallpox vaccine reactions. The applicant has advised that sufficient VIG to treat three patients has been stockpiled in Singapore and could be shipped to Australia within 24 hours.

More VIG can be provided to the Singapore depot as needed.

88.

The antiviral drug Cidofovir may be considered as a second line treatment for the adverse

reactions listed in paragraph 86. While Cidofovir has shown anti-poxviral activity

in vitro and in mice, it has not been used to treat VACV infection in humans (Maurer et al. 2003; Wittek

2006). It can also have severe side effects, including irreversible renal toxicity (Enserink 2002).

The US CDC recommends its use only where all VIG supplies are exhausted, a patient fails to improve with VIG treatment, or for patients near death (Centers for Disease Control and

Prevention 2003). Cidofovir is available in Australia but is not approved for the treatment of vaccinia-related complications; off-label use would thus be required. The applicant has advised that it could be included on the Clinical Trial Notification as a rescue medication for this study.

4.3.5 Contraindications for use of smallpox vaccine (VACV)

89.

The specific conditions associated with the adverse reactions described in Section 4.3.3

are contra-indications for smallpox vaccination. People who should not be exposed to VACV are those:

 with a history or presence of eczema or atopic dermatitis;

 with other acute, chronic or exfoliative skin conditions;

 with conditions associated with immunosuppression;

 who are pregnant or breast-feeding;



 who are aged less than one year; or

 who have a serious allergy to any component of the vaccine (Wharton et al. 2003).

4.4 VACV shedding from infected hosts

90.

In the context of smallpox vaccination, VACV can be shed from the primary lesion from at least the third to twenty first days post-vaccination – from the time the papule develops until the scab drops off, and possibly longer. Maximal shedding occurs between days 4 and 14, and peak titres of 10

7

pfu/ml have been detected (Cummings et al. 2008; Cooney et al. 1991;

Wharton et al. 2003).

91.

Limited historical data suggests that viremia (viral presence in the blood), viruria (viral presence in urine) and pharyngeal shedding in association with the NYCBH strain were uncommon, although such reactions were documented with more virulent vaccine strains used in Europe and Asia (e.g. (Gurvich et al. 1974)). Viremia and viruria do occur in patients with

progressive vaccinia and eczema vaccinatum (see Section 4.3.3) (Lane & Fulginiti 2003).

92.

In the context of non-human hosts, VACV is shed into the milk of infected dairy cattle. It should be noted that viral lesions occur on the udders, however virus continues to be detected in milk even after these lesions have healed (Rehfeld et al. 2015).

4.5 Host to host transmission

93.

VACV is generally transmitted through direct physical contact with a lesion or vaccine inoculation site, or contact with a contaminated object (e.g. bandages, clothing, sheets and towels). An infected person may spread the virus from the site of initial infection by touching other body parts or people with contaminated hands, or through such every day activities as shaving (Armed Forces Health Surveillance Center (AFHSC) 2014; CDC 2013; Egan et al.

2004; Oliveira G.P et al. 2014). Transmission usually required close interaction and occurred most often in the home (Wharton et al. 2003). Zoonotic transmission through direct physical contact has also been documented during outbreaks of bovine vaccinia in South America (Lum et al. 1967; Silva-Fernandes et al. 2009).

94.

Oral transmission via drinking contaminated milk has been observed in humans

(Damaso, 2000) and demonstrated experimentally in mice (Rehfeld et al. 2015). A VACV-

based rabies vaccine (discussed in Section 5.2.1) also relies on oral transmission for efficacy.

95.

Natural infections with other orthopox viruses such as variola virus (smallpox) commonly occur via the respiratory tract (Fenner 1989). However, in the context of vaccination with the NYCBH strain, aerosol transmission of VACV is considered unlikely and has not been documented. The millions of vaccinations performed in the past provided extensive opportunity for viral spread within families. However, relatively few transmissions were reported and all involved physical contact. Airborne transmission has never been documented (Lane & Goldstein 2003a; Lane & Fulginiti 2003).

96.

Average transmission rates from historical smallpox vaccination campaigns in the USA and UK are reported as 20-60 per million primary vaccinations (Neff et al. 2002). However, vaccinees were generally young children and the majority of contacts would have been immune or had previous exposure to vaccinia due to ongoing vaccination campaigns.

Therefore, not every exposure would have resulted in observable infection. While it would be reasonable to expect a higher transmission rate from adults to the predominantly unvaccinated population of today, a recent report estimates that, among health care workers and military personnel vaccinated between 2003 and 2011, the rate of transmission to non-vaccinees was still 54 per million vaccinees (Wertheimer et al. 2012).

97.

Reported cases predominantly involved transmission between family members or other close contacts (e.g. school friends), and transmission in a hospital setting. The latter involved


Office of the Gene Technology Regulator transmission to clusters of patients from recently vaccinated health care workers or patients hospitalised with a vaccine-related complication (Sepkowitz 2003). In more recent (post-2000) vaccination programmes involving health care workers in Israel and the USA, there were no reports of transmission to patients (Lane & Fulginiti 2003).

4.6 VACV persistence in infected hosts

98.

VACV is thought unable to persist in a latent state within an infected host. The large poxviral genome is apparently unstable in host cells, and the large size of virus particles encourages their clearance by phagocytic cells of the immune system (Buller & Palumbo

1991).

4.7 VACV-host interactions

99.

VACV infection in immune-competent hosts is generally self-limiting and involves an interplay between the host immune response and viral evasion strategies in which the host ultimately prevails.

100.

The host response to VACV infection is multifactorial. Immediately after viral invasion, nonspecific mechanisms such as apoptosis induction, complement, interferons, cytokines and natural killer cells serve as a first line of defense. Subsequently, adaptive immune responses mediated by cytotoxic and helper T cells develop. Although neutralizing antibodies contribute to host protection (especially in preventing subsequent infection with VACV), the T cell response is particularly potent and may be critical for viral clearance. The response is mediated by T helper 1 (T h

1) cells, which enhance the cytolytic activity of macrophages and cytotoxic T cells which can then kill virally infected cells. In contrast, development of a T h

2 response, which promotes antibody production, may actually suppress viral clearance.

101.

To counter host immunity, VACV deploys a range of immune evasion strategies that suppress innate immunity and the T h

1 immune response. These include interference with antigen presentation to T cells, inhibiting complement activation and suppressing apoptosis of infected cells. These tactics allow VACV to infect its hosts and replicate with high efficiency

(Owen et al. 2013; Shen & Nemunaitis 2005; Thorne et al. 2005)

4.8 Recombination with other poxviruses

102.

Homologous recombination between vaccinia strains (Fenner & COMBEN 1958), and between vaccinia and other poxviral species (WOODROOFE & Fenner 1960), has been demonstrated in vitro , and requires both viruses to be present and replicating within the same infected host cell. The ability to recombine with cytoplasmic nucleic acid forms the basis of the molecular biology techniques used in constructing the GM virus described in this application

(Nakano et al. 1982; Weir et al. 1982).

103.

Genetic recombination appears to have occurred in nature between other orthopoxviruses

(Gershon et al. 1989). Several examples that suggest horizontal gene transfer (HGT) into

VACV have also been reported: two cowpox virus -like genes are present in VACV Lister strain (Garcel et al. 2007) and a small horsepox virus -like region was identified in a Dryvax subclone (Qin et al. 2011). It was once common to periodically cocultivate smallpox vaccine strains with other orthopoxviruses so as to “refresh” their efficacy - a practice that could well have produced recombinants (Qin et al. 2011).

104.

Although replicating poxviruses can recombine very efficiently under certain circumstances, there are physical constraints within a cell that limit recombination between coinfecting viruses. Poxvirus replication and virion assembly takes place in intracellular structures called virosomes, which appear to limit the fusion of co-infecting viral particles and the mixing of different viral DNAs (Lin & Evans 2010).



4.9 Susceptibility of VACV to disinfectants

105.

Purified VACV is inactivated within 1 minute by a range of common chemical disinfectants including 70% ethanol, 50% isopropyl alcohol and 0.5% sodium hypochlorite

(Chambers et al. 2009).

106.

Vaccinia samples on hands were disinfected by 2-5 minutes contact with 1.5% chloramine T or 70% isopropylalcohol (Schumann & Grossgebauer 1977), and showed 99.99% reduction in titre from a 30 second hand wash in disinfectants containing greater than 75% ethanol (Kampf et al. 2007).

107.

The US CDC Advisory Committee on Immunization Practices (ACIP) and Healthcare

Infection Control Practices Advisory Committee (HICPAC) recommend that appropriate hand hygiene after contact with items that may be contaminated with VACV includes washing with antimicrobial soap and water or an approved alcohol-based hand-rub containing 60% alcohol or more (Wharton et al. 2003).

4.10 Survival of VACV in the environment

108.

Poxviruses are well known for their ability to persist in the environment. They are highly resistant to drying and, historically bedding, clothes and personal effects belonging to smallpox patients remained contagious for several years. Their stability is enhanced by the materials in which they are introduced into the environment: scabs, serum, blood and other proteinaceous secretions (Rheinbaben et al. 2007; Wood et al. 2013).

109.

Poxviruses are more tolerant of increased temperature than other enveloped viruses and their environmental resistance at ambient temperature is high. VACV shed in mouse faeces can remain viable for 20 days or more (Abrahão et al. 2009), and VACV in scabs remains viable for over eight weeks at 35 ° C. Virus from patients is commonly more resistant than virus isolated from cell culture. Cell-bound cultured virus is in turn more resistant than purified virus preparations isolated from culture supernatants (Rheinbaben et al. 2007).

110.

At lower temperatures, poxviral stability is even higher. Dried VACV particles can be stored at 4 ° C for over 35 weeks with no loss of infectivity, and VACV in storm water remained viable at 4.5

° C for close to 6 months. When stored frozen (-20 ° C), one in one thousand virus particles remained viable after 15 years (Essbauer et al. 2007; Rheinbaben et al. 2007).

Section 5 The GMO – nature and effect of the genetic modification

5.1 Introduction to the GMO

111.

The GMO was first described by Mastrangelo and colleagues as a vehicle for intratumoural expression of human granulocyte-macrophage colony-stimulating factor (hGM-CSF).

Their objective was to facilitate the presentation of tumour antigens to the immune system in an environment favourable for developing systemic anti-tumour immunity (Mastrangelo et al.

2000a; Mastrangelo et al. 1998).

112.

VACV was used as the vector due to its high infection efficiency and broad cell tropism that offered potential for therapeutic use against tumours of diverse origin. In addition, its ability to replicate in and lyse cells, releasing infectious progeny, was anticipated to amplify its effectiveness over that of the initial dose alone. GM-CSF was selected from amongst several immunogenic cytokines as earlier work had shown that a tumour vaccine expressing GM-CSF conferred anti-tumour immunity more effectively than vaccines expressing other immunogenic cytokines (Dranoff 2003). Furthermore, GM-CSF had been used clinically in cancer patients and was considered safe and effective in this context.

113.

The GMO was produced by homologous recombination into the viral TK gene (a commonly used locus), disrupting the TK sequence and introducing the hGM-CSF and E. coli


Office of the Gene Technology Regulator lacZ genes. The latter, encoding the β-galactosidase enzyme, was included as a marker to enable infected cells to be detected histochemically and immunologically. On the basis of prior clinical experience with both Dryvax TM VACV and GM-CSF, the GM virus was tested directly in patients with metastatic melanoma. No prior in vitro or animal studies have been published

(Mastrangelo et al. 1998).

114.

The GMO has subsequently been investigated as an oncolytic virus (OV) on the basis of preferential replication in and destruction of tumour cells, while also stimulating a systemic anti-tumoral immune response through the expression of the introduced hGM-CSF gene

(reviewed in (Breitbach et al. 2012; Breitbach et al. 2015; Merrick et al. 2009).

5.2 The genetic modifications and their associated effects

115.

The GMO was constructed using standard molecular biology techniques. Briefly, the hGM-CSF and lacZ genes, flanked by VACV TK sequences, were cloned into a plasmid. The plasmid was transfected into cultured mammalian cells already infected with the parent virus preparation (Dryvax

TM

), allowing the two foreign genes to integrate into the viral TK gene through homologous recombination (Figure 2). A single virus clone containing the desired genetic change was isolated by plaque purification.

Figure 3.

Structure of the modified region of the JX-594 genome (from (Mastrangelo et al. 1998)).

5.2.1 Disruption of Thymidine Kinase gene

116.

Thymidine kinase (TK), encoded by the TK gene, is an enzyme found in most living cells, and some viruses, that catalyses the transfer of the terminal phosphoryl moiety from adenosine triphosphate (ATP) to deoxythymidine (dT), yielding deoxythymidine monophosphate (dTMP) (El Omari et al. 2006). This is a necessary step in the production of deoxythymidine triphosphate (dTTP), one of the four nucleotides that make up the DNA molecule.

117.

Normal cells express TK when preparing to actively divide: it is low or absent in resting cells, starts to appear in late G

1

phase, increases in S phase and disappears during mitosis

(Welin et al. 2004). The role of viral TK is to generate sufficient dTTP for viral DNA synthesis in host cells that are not actively dividing.

118.

The VACV TK gene encodes a 19 kDa polypeptide of 177 amino acids (Weir, 1983) which folds into a protein with two domains: a larger N-terminal α/β-domain and a smaller zinc-containing domain. Binding of the substrates (ATP and dT) involves both domains (El

Omari et al. 2006; Welin et al. 2004). The functional enzyme is a homotetramer of TK monomers.

119.

The introduced genes disrupt the TK gene partway through the region encoding the

N-terminal domain. Mastrangelo et al. (2000) reported that at least part of the viral TK sequence is still transcribed (Mastrangelo et al. 2000a). However, a partial TK polypeptide sequence, if translated, is unlikely to fold correctly and would be degraded by the cell. No TK sequence has been deleted in the GM virus.



120.

Loss of viral TK function leaves the virus dependent on host cell nucleotides, which are typically found in dividing cells and in greatest abundance in tumours (Autio et al. 2014; Zeh

& Bartlett 2002). Accordingly, the GM virus is expected to replicate preferentially in these cell types.

121.

This strategy has been employed in the design of other oncolytic viruses, for example, the GM herpes simplex virus 1 (known as Talimogene laherparepvec), recently approved by the Regulator for commercial supply (DIR 132) subject to its approval by the Therapeutic

Goods Administration as a cancer therapeutic.

122.

No in vivo data directly comparing the GM virus with unmodified VACV (either the

Dryvax

®

preparation or the specific parental clone) is available, either in tumour models or healthy subjects. However, in the context of other VACV strains, constructs with a disrupted or deleted TK gene generally show attenuation relative to the parent virus. Some examples are discussed below.

123.

Buller and colleagues were the first to show that disruption of the VACV TK gene during homologous recombination significantly attenuated the recombinant virus.

However, the route of exposure influenced the outcome. TK recombinants were less pathogenic than their parent virus when introduced intracerebrally or intraperitoneally into mice but, when introduced intradermally, TK disruption did not affect viral replication

(Buller et al. 1986).

124.

In contrast, Naik and coworkers found that TK-disruption attenuated the highly virulent Western Reserve (WR) strain of VACV when introduced intradermally into nonhuman primates (rhesus macaques). The area of necrosis produced by the virus was greatly reduced by TK disruption, although a significant lesion still formed. The less pathogenic

Wyeth strain produced only a small lesion that was, in fact, slightly larger in response to the

TK

-

form (Naik et al. 2006).

125.

The safety of a TK -disrupted GM VACV (Copenhagen strain) towards a wide range of animal and bird species has been extensively studied in the context of the rabies vaccine

Raboral V-RG

®

(V-RG) – a GM VACV in which the rabies glycoprotein gene was inserted within the viral TK gene. Intended for oral vaccination of wild animals, it has been distributed widely in the environment in Europe and North America since 1987 and 1995, respectively.

126.

V-RG and the parental VACV Copenhagen strain displayed similar pathogenicity towards non-human primates after transdermal inoculation. Both viruses caused lesions of similar size at the inoculation site which resolved within three weeks, but no signs of systemic illness and no oral or fecal shedding (Rupprecht et al. 1992).

127.

V-RG replicates sufficiently well in target species (red foxes, raccoons and striped skunks) to induce high level immunity to rabies, but no vaccinia-related pathogenicity has been observed at any dose or by any route of administration tested (oral, intramuscular, intraduodenal, subcutaneous, intradermal, conjunctival and intranasal). When administered intradermally to foxes, the cutaneous reaction was significantly reduced relative to the reaction to unmodified VACV (Copenhagen strain), however orally administered unmodified and TK viruses behaved similarly – neither one spread beyond the oral cavity or persisted beyond 48 hours, and viral titres were very low (Blancou et al. 1986; Brochier et al. 1989; Pastoret &

Brochier 1996; Rupprecht et al. 1988; Thomas et al. 1990).

128.

The safety of orally-administered V-RG has also been demonstrated in non-target species including wild boars, badgers, bats, coyotes, and a range of rodent and bird species. Sufficient viral replication for seroconversion took place, however there were no vaccine-related pox lesions or other clinical signs. Apathogenicity of orally delivered V-RG has also been demonstrated in domestic non-target species including laboratory mice, rabbits, ferrets, cattle, cats, dogs and sheep (Artois et al. 1990; Brochier et al. 1989).



129.

No horizontal transmission from vaccinated to unvaccinated animals kept in close proximity was detected in the case of foxes, wild boars, badgers and mice. Horizontal transmission between raccoons did occur (Blancou et al. 1986; Brochier et al. 1989; Rupprecht et al. 1988).

130.

It should be noted that immune-compromised individuals may suffer from infection with V-RG. From a small number of human exposures 4 , two case reports of serious human infection involving at-risk individuals have been published. In both cases, the route of exposure was transdermal and resulted from handling a ruptured bait sachet found by their dog. The first case involved a pregnant woman with a chronic skin condition who did not wash the site of exposure and developed necrotic lesions, redness and swelling of the affected limb and enlargement of the draining lymph nodes, followed by generalized erythroderma

5

and sloughing of skin from her face, neck, palms and soles. She was hospitalised but not initially diagnosed with vaccinia infection. The lesions were surgically removed and she recovered 34 days post- exposure (Rupprecht et al. 2001). In a second case, a woman taking immunosuppressive medication developed a spreading pustular infection, required two weeks hospitalization and was treated with VIG due to concerns about progressive vaccinia (Dato et al. 2009). In the laboratory setting, experiments with immunodeficient mice showed that orally delivered V-RG was nonpathogenic but parenteral (transdermal, intramuscular and intraperitoneal) exposure led to systemic and progressive infection, albeit less severe than caused by unmodified VACV

(Hanlon, 1997).

5.2.2 Introduction of the hGM-CSF gene

131.

The gene encoding hGM-CSF has been inserted within the VACV TK gene. GM-CSF is a haematopoietic growth factor produced by a wide range of cell types in response to specific signals. It plays a redundant role in stimulating the development and differentiation of myeloid cells. In addition, it has a range of pro-inflammatory effects on mature haematopoietic cells and is involved in the development of inflammatory and autoimmune diseases (reviewed in

(Shiomi & Usui 2015)).

132.

hGM-CSF gene expression is driven by the non-coding synthetic early-late VACV promoter (Chakrabarti et al. 1997). This promoter has been widely used to direct gene expression throughout the full VACV lifecycle (Baur et al. 2010). Promoter activation is stronger and more sustained in the later stages of the viral lifecycle, thus tying high expression of the transgene to viral replication (Hwang et al. 2011).

133.

Expression of hGM-CSF within the inoculated tumour is intended to attract and activate dendritic cells. These are antigen presenting cells which can take up and present tumour

4 In a 2001 report on exposures to environmentally-distributed Raboral V-RG

®

vaccine in Ohio during 1990-2000,

160 instances of human contact with baits containing the vaccine (2ml liquid in a plastic sachet) were cited. In twenty cases, humans were potentially exposed to vaccine due to rupture of the sachet. Two exposed people listed

a contraindicated health condition – one being the first case discussed in paragraph 130. The second (a pregnant

woman) washed her hands after touching the bait and no adverse consequences were reported (Rupprecht et al.

2001). The second case discussed above was associated with a US wildlife vaccination program running from

2003-2009. In 2008, 291 instances of human or domestic animal contact with baits were reported. The article does not indicate how many of these involved human exposure to the vaccine or contraindicated conditions. The patient described was the only documented case of vaccinia infection associated with this baiting program.

5 Erythroderma is an inflammatory skin disorder characterised by intense redness and scaling, and typically involves almost the whole body surface. Severe cases can be fatal even when properly managed due to metabolic burden and complications (Okoduwa et al. 2009).


Office of the Gene Technology Regulator antigens released by viral lysis of tumour cells, thus stimulating a specific anti-tumour immune response. hGM-CSF was selected over other cytokines for two reasons: (1) it was the most potent stimulator of anti-tumour immunity of a number tested; and (2) prior clinical experience with its use in cancer patients (Dranoff 2003; Mastrangelo et al. 2000a).

134.

hGM-CSF exhibits a degree of species-specificity. It is inactive in mice (Kaushansky et al. 1989; Lee et al. 1985), however is active on canine cells and displays limited cross reactivity in cats (Dunham & Bruce 2004; Mayer et al. 1990). The activity of hGM-CSF in other species is not known.

135.

Purified recombinant hGM-CSF(Leukine®) is a United States Food and Drug

Administration-approved pharmaceutical used to reconstitute depleted myeloid cells in certain types of cancer patients and after bone marrow transplants. It is viewed as safe for use in cancer patients, but is associated with a number of side effects.

136.

At clinically relevant doses (5-10

 g/kg/day), mild-moderate adverse reactions occur in

20-30% of patients and commonly include fever, myalgia, malaise, bone pain, rash and local reaction at the injection site. Skin reactions usually resolve within a few days of discontinuing

GM-CSF. Severe reactions are rare (less than a few percent). Early clinical trials using doses above 10

 g/kg were associated with a greater incidence of mild-moderate effects and also the presentation of serious adverse reactions (Stern & Jones 1992).

137.

Serum levels of hGM-CSF following therapeutic doses of the cytokine exceed 1 ng/ml

(Cebon et al. 1992). In clinical trials of the GMO, detectable levels of circulating hGM-CSF protein have been generated in many patients, with a small percentage reaching systemic levels similar to those associated with therapeutic doses (Park et al. 2015; Park et al. 2008).

138.

In vivo , GM-CSF inoculation is associated with a local influx of immature dividing monocytes, granulocytes and activated lymphocytes to the inoculation site. In the tumour context, the immune response is mainly active against cancerous tissue, however a small antiviral response was observed in another recombinant viral system (Grossardt et al. 2013).

139.

In a preclinical study of the GM virus, high doses of JX-594 and a similar construct expressing murine rather than human GM-CSF (mJX-594) were inoculated intracerebrally into rats and mice. Both viruses were well tolerated in mice, but rats responded poorly to mJX-594.

They exhibited poorer grooming and were less active 3-5 days after inoculation, though regained health thereafter. mJX-594 induced more extensive inflammation and tissue necrosis than JX-594, suggesting this was due to GM-CSF expression rather than to the viral infection

(Lun et al. 2010).

140.

hGM-CSF has been introduced into several other recombinant oncolytic viruses intended for cancer treatment, including adenovirus, Newcastle disease virus, herpes simplex virus

(HSV) and measles virus (Grossardt et al. 2013). The Regulator recently approved the commercial supply in Australia of GM herpes simplex virus 1 (known as Talimogene laherparepvec) expressing hGM-CSF and intended as a prescription-only cancer therapeutic

6

.

Therapeutic use of Talimogene laherparepvec is subject to approval by the Therapeutic Goods

Administration.

5.2.3 Introduction of E. coli LacZ gene

141.

The bacterial lacZ gene encodes the enzyme



-D-galactoside galactohydrolase (



galactosidase), which hydrolyses b-galactosidic bonds in sugars such as lactose. It is part of the

6 The Risk Assessment and Risk Management Plan for DIR-132 is available at http://www.ogtr.gov.au/internet/ogtr/publishing.nsf/Content/DIR132


Office of the Gene Technology Regulator lac operon (lactose operon) found in E. coli and many other enteric bacteria. While glucose is the preferred carbon source for most bacteria, the lac operon allows for digestion of lactose when glucose is not available.

142.

The lacZ gene has a long history as a marker or reporter of promoter activity, as the



-galactosidase enzyme can be detected using a simple biochemical test. It has been expressed both ubiquitously and in selected tissues in transgenic mice, and does not cause obvious phenotypic changes or toxicity (Beddington et al. 1989; Suemori et al. 1990; Zambrowicz et al.

1997; Savatier et al. 1990).

143.

The lacZ gene has been expressed in a variety of cell types in different species, including cotton rats and non-human primates. Cells expressing this reporter gene have also been safely introduced into humans (Puumalainen et al. 1998).

144.

In the GM virus, expression of the lacZ gene is driven by the p7.5 VACV promoter. As this is a constitutive early/late promoter, the LacZ gene product would be expressed both early and late in the virus life cycle (Baur et al. 2010)

5.2.4 Toxicity or adverse response associated with the genetic modifications

145.

The GM virus is intended for clinical use as a therapeutic agent for patients with, in this clinical trial, advanced HCC. It is cytotoxic for infected tumour cells as the viral replication cycle ends in cell lysis. In addition, the GM virus is intended to stimulate a systemic antitumour immune response, directed at both infected and non-infected tumour cells.

146.

Should the residual TK gene be translated, it is not expected to fold correctly and would likely be degraded within the cell (see Section 5.2.1). Therefore, it is not expected to give rise to a toxin or allergen.

147.

hGM-CSF is an unmodified human protein that is an FDA-approved therapeutic product for cancer patients. As such, it is not a toxin or allergen. However, it is a pro-inflammatory cytokine and when present systemically at sufficient concentration, leads to the type of adverse reaction described in Section 5.2.2. When delivered locally, it stimulates localised inflammation (Lun et al. 2010). It displays limited cross-reactivity with other species (Section

5.2.2).

5.3 Characterisation of the GM virus

5.3.1 Genotype stability and molecular characterisation of the GM virus

148.

As no sequence was deleted from the TK gene in constructing the GM virus, it is possible that JX-594 could revert to the wild-type VACV sequence by eliminating the entire inserted expression cassette. However, genetic stability studies have not detected spontaneous reversion. The applicant has stated that each batch of GM virus produced is tested for retention of the hGM-CSF/LacZ insert by real-time PCR using a primer pair that detects TK

+

viral genomes. To date, five lots have been tested and all have been negative for TK + virus.

149.



-galactosidase enzyme activity is also used as a marker of genomic integrity. Over 500 viral plaques from two clinical lots of JX-594 have been assessed, yielding 99.86% and 100% positive plaques.

5.3.2 Transmissibility of the GM Virus

150.

There is little restriction on VACV entry into cells – permissiveness is at the level of survival and replication once inside the cell. Disruption of the viral TK gene renders the GM virus dependent for replication on cellular deoxythymidine. The GMO is therefore expected to replicate most effectively in cells with a high intracellular nucleoside pool. These are most likely to be cancer cells, followed by normally dividing cells. The GMO is expected to infect the same range of cells as the unmodified virus, and at the species level, the host range is unlikely to differ from that of unmodified VACV.



5.3.3 Non-clinical studies of the GMO

151.

A safety study was performed in New Zealand White rabbits by intravenous infusion of one or three weekly doses of JX-594 (Kim et al. 2006). Doses of 4x10

8

pfu/kg were well tolerated; the only overt clinical sign observed over a 92 day period was a small initial weight loss that was regained over the next four weeks. There were no major toxicological findings.

Mild inflammation in the liver and lungs, and mild follicular hyperplasia in the spleen were observed at day 4, when viral replication was expected to be maximal. Lymphoid hyperplasia increased over time but resolved by the end of the study (92 days). These findings are consistent with mild VACV infection (inflammation) and with expression of the hGM-CSF transgene (lymphoid hyperplasia).

152.

As blood cells will come into contact with the GM virus, either via IV infusion or during secondary spread following in vivo replication, the GMO has been assessed for its ability to infect them. Parato and colleagues demonstrated that JX-594 replicates in neither resting nor activated peripheral blood mononuclear cells (PBMCs) isolated from human blood (Parato et al. 2012).

153.

To examine the tumour selectivity of the GM virus, the ex vivo sensitivity of human tumour biopsy material and companion normal tissue were compared. Tumour tissue was more sensitive to JX-594 infection than the normal tissue counterpart (Breitbach et al. 2011; Parato et al. 2012). Tissue selectivity was also assessed in a transgenic mouse model of ovarian cancer. When mice were treated intraperitoneally with a version of the GM virus in which the lacZ gene was replaced by the luciferase marker gene, luciferase expression was concentrated in the cancerous region (Parato et al. 2012).

154.

To examine the efficacy of the GM virus, JX-594 was tested in a rabbit liver cancer model. A single dose of the GMO was delivered either by direct injection into the liver tumour or by intravenous infusion to target both primary tumour and lung metastases. JX-594 delivered by either method slowed tumour progression and increased survival time significantly, and completely prevented the appearance of metastases (Kim et al. 2006).

155.

JX-594 was further tested for efficacy against carcinogen-induced liver tumours in a rat model. Intravenously delivered JX-594 caused complete tumour regression in 5 of 6 animals, whereas tumours in control animals progressed to a point where the animals were sacrificed for ethical reasons (Kim et al. 2006).

5.3.4 Clinical trials of the GMO

156.

A total of thirteen clinical studies have been or are currently being carried out in North

America, Asia and Europe. Approximately 300 patients have received the GMO in 1200 treatments of varying dose. Seven trials have been completed and published, and relevant information is summarised in Table 2.

Table 2 Summary of published clinical trials.

No. Study Design Patients Comments

1 Phase I open-label uncontrolled study investigating the safety and efficacy of JX-594 delivered by intratumoural (IT) injection.

Twice weekly escalating dose treatments

(1x10 4 – 8x10 7 pfu) for at least six weeks.

Treatment of patients with unresectable stage

3-4 malignant melanoma.

Trial ID: BB-IND 6486

7

Reference

Mild flu-like symptoms developed within 4-6 hours of higher dose treatments (>=4x10 7 pfu) and resolved within 24 hours.

Local toxicity: dose-dependent inflammation of injected tumours.

Pustules: not discussed.

(Mastrangelo et al. 2000b)



No. Study Design

2

3

4

5

6

Phase I/II open-label, multi-centre study investigating the safety and mechanism of action of JX-594 delivered by IT injection.

Six treatments at weekly intervals. Single dose (1x10 8 pfu).

Treatment of patients with unresectable stage

3-4 malignant melanoma.

Trial ID: NCT00429312; JX594-IT-HEP001

Phase I open-label study to determine maximum tolerated dose and assess the safety of JX-594 delivered by IT injection.

Two to four treatments at three week intervals. Four doses (range 1x10 8 - 3x10 9 ).

Treatment of patients with unresectable primary or metastatic tumours in the liver.

Trial ID: NCT00629759; JX594-MEL005

Phase I open-label multi-centre study to determine the maximum tolerated dose of JX-

594 delivered by intravenous (IV) infusion.

Single treatment at one of six dose levels

(1x10 5 – 3x10 7 pfu/kg).

Treatment of patients with advanced/metastatic solid tumours of various origin, refractory to standard therapy.

Trial ID: NCT00625456; JX594-IV-011

Phase I open-label study to determine the maximum tolerated dose and investigate the safety of JX-594 delivered by IT injection.

1-2 treatments at one of two doses (1x10 6 /kg and 1x10 7 /kg).

Treatment of pediatric patients (age 4-21 years) with advanced or metastatic, unresectable solid tumours of various origin.

Trial ID: NCT01169584; JX594-IT-P009

Phase IB open-label study to determine the maximum tolerated dose and investigate the safety of JX-594 delivered by IV infusion.

2-4 treatments at two week intervals, at one of three doses (range 1x10 6 – 3x10 7 pfu/kg).

Treatment of patients with advanced, refractory colorectal carcinoma.

Patients Comments

10

14

23

6

15

Reference

All patients experienced at least one adverse event. Mildmoderate flu-like symptoms were most common. One case each of severe hypoglycaemia, fever and anaemia. All were transient.

Circulating viral genomes detected in 50% of patients 5-7 days after initial inoculation.


(Hwang et al.

2011)

All patients experienced mildmoderate flu-like symptoms 4-16 hours after treatment.

Dose-limiting toxicities at highest dose (3x10 9 pfu) (see paragraph

157).

Circulating viral genomes detected in 12/14 patients between days 3 and 22 postinoculation.


Shedding: no virus detected in urine or throat swabs.

(Park et al. 2008)

(Liu et al. 2008)

(patients with

HCC only)

Most common adverse events were mild flu-like symptoms lasting up to 24 hours.

No dose-limiting toxicities.

Viral replication in tumours but not surrounding tissue.

Pustules: a single skin pustule developed in each of two patients one week after infusion and resolved without sequelae.

Treatment dose not reported.

Shedding: see Section 5.3.6.

(Breitbach et al.

2011) (Breitbach et al. 2013)

Mild-moderate flu-like symptoms beginning at 6-10 hours and resolving by 24 hours.

Pustules: developed in all three patients receiving the higher dose (ages 10, 18, 21 years).

Developed within a week and resolved after 3-4 weeks.

(Cripe et al. 2015)

All patients experienced mild flulike symptoms, generally lasting less than 24 hours.

No dose-limiting toxicities.

Pustules: developed in 7/9 patients receiving the highest dose and none at the two lower doses. Appeared on days 3-7 of

(Park et al. 2015)



No. Study Design

7

Trial ID: NCT01469611; SMC IRB 2009-06-

055

Phase IIA open-label study investigating the safety, tolerability and efficacy of JX-594 delivered by IT injection.

Three treatments at fortnightly intervals, at low or high dose (1x10 8 or 1x10 9 pfu).

Treatment of patients with unresectable primary hepatocellular carcinoma.

Trial ID: NCT00554372; JX594-IT-HEP007

Patients Comments first cycle and resolved within 5-

26 days. Locations included palms, soles, oral mucosa, lips.

Shedding: no virus detected in urine. Throat swabs positive from days 5-8 in 1/6 lower dose patients and 5/9 at the highest dose. High dose patients with positive throat swabs had active oral or lip pustules at the time.

Reference

30 Mild flu-like symptoms in all patients after 12-24 hours.

One serious adverse event (high dose) – nausea and vomiting with prolonged hospitalisation.

Circulating viral genomes detected in 3/30 patients between days 15-36 postinoculation.

Pustules: 1/16 high dose patients developed 8-10 skin pustules on extremities, face and trunk.

Developed 4 days after treatment and resolved within 6 weeks.

(Heo et al. 2013)

157.

The maximum tolerated dose was 1x10

9

pfu (the dose to be administered in the proposed

Phase 3 trial). Patients receiving a higher dose experienced dose-limiting toxicities of severe abdominal pain, loss of appetite and tissue obstruction due to tumour swelling (Park et al.

2008).

158.

At lower doses of the GMO, mild-moderate flu-like symptoms (e.g. fever, chills, fatigue, headache, myalgia, nausea, vomiting, anorexia , tachycardia, hypotension and hypertension) lasting up to 24 hours were common (Mastrangelo et al. 2000b; Cripe et al. 2015; Heo et al.

2013; Breitbach et al. 2011; Park et al. 2015; Liu et al. 2008; Park et al. 2008). Other adverse effects include transient decreases in lymphocytes, platelets and red blood cells (Park et al.

2008).

159.

Circulating viral genomes were observed immediately and for some hours after intratumoural inoculation. They reappeared in the blood at later time points, consistent with viral replication in and shedding from tumours (Heo et al. 2013; Hwang et al. 2011; Liu et al.

2008; Park et al. 2008).

5.3.5 Pustule formation in the clinical studies

160.

Thirteen (12.4%) of the 105 patients participating in the published clinical trials developed one or more skin or oral pustules 7 within 3-7 days of the first treatment (Figure 3).

Locations included the soles, palms, arms, fingers, torso, face, oral mucosa and lips. All pustules resolved within six weeks or less. Reportedly, skin pustules were not bothersome to

7 The term pustule is hereon intended to mean a viral lesion in any of the progressive stages mentioned in Section

4.3.1


Office of the Gene Technology Regulator the patients and healed without scarring, however oral/lip pustules did cause pain or other discomfort (Cripe et al. 2015; Heo et al. 2013; Breitbach et al. 2011; Park et al. 2015).

Fig. 4. Examples of skin pustules forming after intratumoural (A) and intravenous (B) treatment with JX-594 (from

(Cripe et al. 2015) and (Park et al. 2015)).

161.

Lesions developed after both intravenous and intratumoural inoculation of the GMO, and were reported in four of the seven published trials. In two of the trials where they were reported, inoculation was intravenous (Park, 2015), and in the other two, intratumoural (Cripe et al. 2015). Pustules formed more frequently after intravenous inoculation (9/38 patients) versus intratumoural (4/38 patients). In two of the four trials, their appearance was dosedependent. Cripe and coworkers observed pustules in all three patients receiving the higher of two IT doses (1x10

7

pfu/kg), and in none of the patients who received 1x10

6

pfu/kg (Cripe et al. 2015). Likewise, Park at al. reported pustules in 7/9 patients receiving the highest IV dose

(3x10

7

pfu/kg) and none at either of the lower doses (1x10

6

and 1x10

7

pfu/kg) (Park et al.

2015). These higher doses are comparable with the dose that patients in the proposed trial will receive. It should be noted that in the study by Heo at al., only one of 16 patients receiving

1x10

9

pfu IT developed pustules (Heo et al. 2013), so this reaction has varied markedly between studies.

5.3.6 Shedding of the GM virus in the clinical studies

162.

Viral shedding from inoculated patients was monitored in the Phase I study summarised in row 4 of Table 2. In this trial, the GM virus was administered by intravenous (IV) infusion to patients with advanced, metastatic solid tumours (Breitbach et al. 2011). Each patient received a single treatment at one of six dose levels between 1x10 5 pfu/kg body weight and

1x10

9

pfu in total. Dose-related viral presence and replication was evident in tumour biopsies

8-10 days after treatment.

163.

Viral shedding to the environment was monitored by collecting urine, blood and throat swab samples from all 23 patients at multiple time points over the 28 days post-treatment and testing for the presence of GM virus. No urine samples were confirmed positive for virus, while blood samples were still being assessed at the time of publication. In 25% of patients, all of whom had tumours contacting the upper aerodigestive tract, GM virus was detected in throat swabs at one or two time points during the first 2 weeks after treatment. The remaining 75% of patients tested negative at all times. No correlation with viral dose was reported.

164.

Two patients each developed a single skin pustule, less than 5 mm in diameter, within a week of treatment. Fluid was obtained by either lifting the intact scab or lancing the intact


Office of the Gene Technology Regulator pustule and swabbing. Both samples tested positive for GM virus by plaque-forming assay

(which detects live virus) and PCR.

165.

The applicant has also provided a data summary compiled from multiple clinical trials.

Fluid drawn from intact GMO-related skin lesions contained live GM virus. Throat swabs revealed low levels of the GM virus in 30 of 93 patients 4-8 days after IV infusion of the

GMO. In patients treated intra-tumourally, however, all throat swabs were negative. No GMO was detected in urine samples collected from a total of 62 patients at various times after treatment with JX-594.

Section 6 The receiving environment

6.1 Sites of release

166.

The intended primary receiving environment would be internally-located (liver) tumours within the clinical trial participants. Each patient is to receive a total dose of 1x10

9

pfu distributed between several tumours, administered via image-guided intratumoural injection.

167.

The secondary receiving environment would be the hospital where the GMO is dispensed, administered and waste disposed of. All clinical sites involved in the study would be equipped to handle infectious agents and procedures would be conducted in accordance with

Universal Standard Precautions (World Health Organisation 2007a) and the Australian

Guidelines for the Prevention and Control of Infection in Healthcare (National Health and

Medical Research Council 2010).

168.

The principal route by which the GM virus could enter the wider environment is by shedding from inoculated trial participants once they leave the hospital and return home. The tertiary receiving environment includes the trial participants’ homes and any places they visit during the period when the GM virus is replicating and shedding. Furthermore, as the applicant has proposed that soiled dressings and cleaning materials used in caring for pustules be disposed of with general household waste, landfill sites also form part of the receiving environment.

6.2 Relevant environmental factors

169.

Environmental factors relevant to the potential persistence or spread of the GMO, or the harm it may cause, include the presence of susceptible hosts and any physical conditions that may aid or restrict transmission to these hosts.

170.

Smallpox vaccination was never mandatory in Australia, and ceased worldwide in 1980.

Forty seven percent of Australian residents are under 35 and so would have no pre-existing immunity to VACV. Of Australian residents aged 35 and over, 57% were born in Australia and it is unknown how many would have received the smallpox vaccine. However, the 43% born overseas could have been vaccinated in their country of birth. People vaccinated many years ago may be less susceptible to VACV infection, or infection may be asymptomatic or produce less severe symptoms (Cohen 2001; Hatakeyama et al. 2005).

171.

It is widely acknowledged that people for whom smallpox vaccination is contraindicated are more prevalent in the population today that during the era of mass smallpox vaccination.

For example, 23% of Australian 6-7 year old children have a history of atopic dermatitis (Gold

& Kemp 2005). There are also likely to be significant numbers taking immunosuppressive drugs for disease control (e.g for autoimmune inflammatory conditions), organ transplant recipients and people with HIV-AIDS.

172.

Animals that can or may be infected with the GMO may be present in environments where it could be shed (e.g. patients’ homes) or where contaminated materials may be discarded (e.g. landfill sites). Such animals include domestic pets, rodents, and other wild or feral animals.



6.3 Related viral species in the receiving environment

173.

The presence of related viral species may offer an opportunity for the horizontal transfer of introduced material from the GMO to other organisms in the receiving environment. As orthopoxviruses replicate in the cytoplasm and do not integrate into the genome of infected cells, horizontal transfer of introduced DNA would most likely to be another poxvirus.

174.

Vaccinia virus is not endemic in Australia and is used only for occasional vaccination of laboratory personnel who are required to work with poxviruses. Clinical staff involved in the study will not be vaccinated. It is therefore not expected that trial participants or materials they dispose of would come into contact with unmodified VACV.

175.

Poxviruses of the family Poxviridae, subfamily Chordopoxvirinae infect many native

Australian mammals and reptiles. Aside from an outbreak in common ringtail possums attributed to an orthopoxvirus, these poxviruses have not been characterised. It is considered likely that all mammal and reptile species are susceptible to these viruses (Australian Wildlife

Health Network 2012b). Avian poxviruses are also present in native bird populations

(Australian Wildlife Health Network 2012a).

176.

The myxoma virus (family Poxviridae, genus Leporipoxvirus) specifically infects rabbits and hares (Wang et al. 2004), causing lethal disease in some species. It was introduced into

Australia in the 1950s in an attempt to control the feral rabbit population (Kerr et al. 2013).

6.4 Presence of the hGM-CSF gene and related genes in the environment

177.

The hGM-CSF gene encodes the protein human Granulocyte-Macrophage Colony-

Stimulating Factor (hGM-CSF). GM-CSF homologues are found in all mammalian species, but display a degree of species specificity. For example, hGM-CSF is not active on mouse cells, and mouse GM-CSF is not active on human cells (Kaushansky et al. 1989; Lee et al. 1985).

However, hGM-CSF is active on dog cells and weakly active on bovine cells, indicating that it does not exhibit absolute species specificity (Maliszewski et al. 1988; Mayer et al. 1990).

6.5 Presence of the LacZ gene and related genes in the environment

178.

The bacterial lacZ gene is found in E. coli and other enteric bacteria that reside in the mammalian gut and possess the ability to metabolise lactose.

179.

A related



-galactosidase enzyme is also ubiquitously expressed in mammals. The protein localises to the lysosomes and is distinguished from the bacterial enzyme by a lower pH optimum.

Section 7 Relevant Australian and international approvals

7.1 Australian approvals

7.1.1 Previous approvals by the Gene Technology Regulator

180.

The Regulator has not previously approved any DIR or DNIR licences for dealings with the proposed GMO.

181.

The Regulator recently issued a DIR licence (DIR-132) for the commercial supply of cancer therapeutic Talimogene laherparepvec , a tumour-selective GM virus based on herpes simplex virus 1.

Talimogene laherparepvec also contains an introduced hGM-CSF gene.

182.

The Regulator has also issued a Limited and Controlled DIR licence (DIR-116) for a clinical trial involving a GM VACV and GM fowlpox virus. The purpose of the trial is to evaluate the efficacy of these GMOs in treating prostate cancer.



7.1.2 Approvals by other government agencies

183.

The proposed Phase 3 clinical trial will be notified to the TGA under the Clinical Trials

Notification scheme. An import permit from the Department of Agriculture will also be required.

7.2 International approvals

184.

The GMO has been or is currently being evaluated in thirteen clinical trials in multiple countries, including the USA, Canada, France, Germany, The Republic of Korea, China and

Taiwan. In April 2015, the US Food and Drug Administration agreed to a Special Protocol

Assessment (SPA) of the current Phase 3 clinical trial. Import and controlled release of the

GMO for the same trial was approved by the New Zealand Environmental Protection Authority on 27 October 2015. The GMO has not been approved for commercial use in any country.



Chapter 2 Risk assessment

Section 1 Introduction

185.

The risk assessment identifies and characterises risks to the health and safety of people or to the environment from dealings with GMOs, posed by or as the result of gene technology

(Figure 4). Risks are identified within the context established for the risk assessment (see

Chapter 1), taking into account current scientific and technical knowledge. A consideration of uncertainty, in particular knowledge gaps, occurs throughout the risk assessment process.

Figure 4.

The risk assessment process

186.

Initially, risk identification considers a wide range of circumstances whereby the GMO, or the introduced genetic material, could come into contact with people or the environment.

Consideration of these circumstances leads to postulating plausible causal or exposure pathways that may give rise to harm for people or the environment from dealings with a GMO

(risk scenarios) in the short and long term.

187.

Postulated risk scenarios are screened to identify substantive risks that warrant detailed characterisation. A substantive risk is only identified for further assessment when a risk scenario is considered to have some reasonable chance of causing harm. Pathways that do not lead to harm, or could not plausibly occur, do not advance in the risk assessment process.

188.

A number of risk identification techniques are used by the Regulator and staff of the

OGTR, including checklists, brainstorming, reported international experience and consultation

(OGTR 2013). In conjunction with these techniques, risk scenarios postulated in previous

RARMPs prepared for licence applications of the same and similar GMOs are also considered.

189.

Substantive risks (i.e. those identified for further assessment) are characterised in terms of the potential seriousness of harm (Consequence assessment) and the likelihood of harm

(Likelihood assessment). The level of risk is then estimated from a combination of the

Consequence and Likelihood assessments. Risk evaluation then combines the Consequence

Chapter 2 – Risk assessment 29

Office of the Gene Technology Regulator and Likelihood assessments to determine level of risk and whether risk treatment measures are required. The potential for interactions between risks is also considered.

Section 2 Risk Identification

190.

Postulated risk scenarios incorporate three components (Figure 5): i.

The source of potential harm (risk source) ii.

A plausible causal linkage to potential harm (causal pathway); and iii.

Potential harm to an object of value, people or the environment.

Figure 5.

Risk scenario

191.

In addition, the following factors are taken into account when postulating the relevant risk scenarios for this licence application:

 the proposed dealings, which are import, conduct experiments with, transport or dispose of the GMOs and the possession (including storage), supply and use of the GMOs in the course of any of these dealings;

 the proposed limits, including the extent and scale of the proposed dealings;

 the proposed controls to restrict the spread and persistence of the GMO;

 characteristics of the parent organism;

 routes of exposure to the GMOs, the introduced genes and gene products;

 potential effects of the introduced genes and gene products expressed in the GMOs;

 potential exposure to the introduced genes and gene products from other sources in the environment; and

 the environment at the site(s) of release.

192.

As discussed in Chapter 1, Section 2, the TGA, the trial sponsor, the investigators and the

Human Research Ethics Committee (HREC) all have roles in ensuring the safety of participants under the Therapeutic Goods Act 1989, and the use of a therapeutic good in a clinical trial must be in accordance with the National Statement on the Ethical Conduct in

Research Involving Humans (National Health and Medical Research Council 2013). Therefore, risk scenarios in the current assessment focus primarily on risks posed to people other than those participating in the clinical trial, and to the environment.

193.

Nine risk scenarios were postulated and screened to identify substantive risks. They are

summarised in Table 3, where circumstances that share a number of common features are

grouped together in broader risk categories. In the context of control measures proposed by the applicant, two of the risk scenarios were identified as posing substantive risks which warranted further assessment. More detail on the scenarios not identified as substantive risks is provided later in this Section, while the substantive risks are characterised in Section 3 of this chapter.



Table 3

Summary

of risk scenarios from dealings with the GMO

Risk Scenario

# Risk source Causal pathway

Section 2.1. Increased disease burden

Potential harm

(a) clinical symptoms following direct exposure to the GM virus

1 GM virus i.

Exposure of persons dispensing or administering the GMO in a hospital via:

needle stick/sharps injury;

contact with abraded skin or mucous membranes (esp. eyes)

 ii.

Establishment of viral infection.

Clinical symptoms ranging from mild to severe

(e.g. flu-like illness, formation of pustules, severe adverse reactions).

Substantive risk?

No

Reasons

 The GM virus would be dispensed in a Class II BSC by staff wearing appropriate

PPE and in accordance with approved clinical site procedures.

 The GMO would be administered by trained medical staff wearing appropriate

PPE and in accordance with Standard Universal Precautions and national guidelines.

 The dose received through accidental exposure would be far less than that administered to trial participants.

 Excluding high-risk individuals from handling or administering the GMO would minimise the possibility of a severe adverse reaction.

 The GM virus is likely to be attenuated with respect to its ability to replicate efficiently in non-dividing cells.

 Neither the disrupted gene nor the introduced genes have previously been associated with toxicity in people or animals.

 The introduced LacZ gene encodes the E. coli  -galactosidase enzyme, which has a history of safe use.

 The introduced hGM-CSF gene is a natural human protein. It may stimulate local inflammation if expressed at high levels but symptoms cease once expression ends.

 Inadvertent exposures documented to date did not lead to clinically significant symptoms or require treatment beyond first aid and observation.



Risk Scenario

# Risk source

2 GM virus

Causal pathway i.

Unused GMO or waste containing the

GMO disposed of from clinical site

 ii.

Exposure of persons handling waste to the

GMO.

 iii.


3 GM virus

4 GM virus i.

Exposure of people or animals to the GM virus due to unintentional release during transport or storage

 ii.

Establishment of viral infection i.

ii.

iii.

iv.

Treatment of trial participant with the

GMO



Samples containing GMO collected from trial participant



Laboratory staff exposed to GMO during analysis



Establishment of viral infection

Potential harm




(e.g. flu-like illness, formation of pustules, severe adverse reactions)


No

No



No

Reasons

 Contaminated waste will be placed in appropriately labelled clinical waste containers and disposed of as infectious clinical waste.

 As noted in Scenario 1, inadvertent exposure to the GMO is likely to involve a low dose , the GMO is likely to be attenuated; the introduced genes have not been associated with toxicity; any local inflammation which may be caused by expression of the introduced hGM-CSF gene would cease once expression ends; and previous inadvertent exposures have not lead to clinically significant outcomes.

 Transport to clinical sites will follow appropriate standards for medical products.

 The GMO will be double-contained for internal transport within clinical sites and a spills procedure will be in place.

 Storage will be at secure storage or clinical facilities.

 All stocks of the GMO will be accounted for, and all unused GMO will be destroyed or returned to the trial sponsor when the study is complete.

 As noted in Scenario 1, inadvertent exposure to the GMO is likely to involve a low dose, the GMO is likely to be attenuated; the introduced genes have not been associated with toxicity; any local inflammation which may be caused by expression of the introduced hGM-CSF gene would cease once expression ends; and previous inadvertent exposures have not lead to clinically significant outcomes.

 Sample testing would be conducted by qualified personnel in pathology or other testing laboratories, which are required to adhere to national standards for handling of infectious substances.

 As noted in Scenario 1, inadvertent exposure to the GMO is likely to involve a low dose, the GM virus is likely to be attenuated; the introduced genes have not been associated with toxicity; any local inflammation which may be caused by expression of the introduced hGM-CSF gene would cease once expression ends; and previous inadvertent exposures have not lead to clinically significant outcomes.



Risk Scenario

# Risk source Causal pathway Potential harm

(b) clinical symptoms following exposure to GM virus shed from trial participants


5 GM virus i.

Treatment of trial participant with the GMO

 ii.

Trial participant develops pustular lesions and sheds the GMO

 iii.

Exposure of clinical/hospital staff or other patients to trial participant shedding the

GMO

 iv.



(e.g. flu-like illness, formation of pustules, severe adverse reactions)

No

6 GM virus i.


 ii.


 iii.

Exposure of people (e.g. carers or household contacts), other than at-risk people, or animals (e.g. domestic pets) through contact with trial participant or contaminated items (e.g. contaminated dressings) outside the clinical/hospital setting

 iv.




No

Reasons

 Patient management would be by qualified clinical staff in accordance with

Standard Universal Precautions (where no lesions are present), with the addition

(where lesions develop) of Contact Precautions appropriate for each clinical site.

 Clinical sites will be expected to develop and implement appropriate precautions to minimise contact between study participants and other patients.

 Excluding high-risk individuals from caring for patients with lesions would minimise the possibility of a severe adverse reaction.



As noted in Scenario 1 the GM virus is likely to be attenuated; the introduced genes have not been associated with toxicity; any local inflammation which may be caused by expression of the introduced hGM-CSF gene would cease once expression ends; and previous inadvertent exposures have not lead to clinically significant outcomes.

 Trial participants will be instructed in well-established hygiene practices known to minimise inadvertent transmission of the parent virus (VACV).

 Patients will be instructed to seal contaminated waste in a primary container

(e.g. plastic bag) when changing dressings at home.

 As noted in Scenario 1, the GM virus is likely to be attenuated; the introduced genes have not been associated with toxicity; any local inflammation which may be caused by expression of the introduced hGM-CSF gene would cease once expression ends; and previous inadvertent exposures have not lead to clinically significant outcomes.

 Transmission to human non-trial participants not reported in previous clinical trials (involving over 300 patients and 1200 administration events).



Risk Scenario

# Risk source

7 GM virus

Causal pathway i.


 ii.


 iii.

Exposure of at-risk people (such as pregnant women, those with a severe inflammatory skin condition or a history of eczema, and the immunocompromised; e.g. carers or household contacts) through contact with trial participant or contaminated items (e.g. contaminated dressings) outside the clinical/hospital setting

 iv.


8 GM virus i.


 ii.

Trial participant develops pustular lesions and sheds the GMO;

 iii.

Material (e.g. used dressing) contaminated with the GM virus enters general waste;

 iv.

Exposure of people or animals in the environment to contaminated material;

 v.


Potential harm

Marginal to severe clinical symptoms


Yes

Reasons

 Some trial participants may develop lesions, leading to shedding of the GM virus.

 If trial participants don’t immediately recognise these lesions, there is potential for any at-risk people with whom they have close contact to be exposed to the

GMO.

 There is uncertainty about the consequences for at-risk people exposed to the

GM virus.

See Section 3.1 for risk characterisation.

Clinical symptoms in people or animals.

Secondary transmission.

Yes  If trial participants dispose of dressings contaminated with the GM virus in general waste, people involved in waste handling may be exposed.

 There is uncertainty about the consequences for at-risk people exposed to the

GMO.

See Section 3.2 for risk characterisation.



Risk Scenario

# Risk source Causal pathway

Section 2.2: Horizontal transfer of genes or genetic elements

9 GM virus i.

Exposure of people or animals to the GM virus leading to infection (see risk

Scenarios 1-8)

 ii.

Person or animal also infected with another related virus

 iii.

Both viruses infect and replicate in the same host cell

 iv.

Recombination between viral genomes takes place

 v.

Recombinant virus infects other hosts

Potential harm

Disease in humans or animals.

Establishment of novel virus in environment.


No

Reasons

 There is no reservoir of VACV in the Australian environment and limited opportunity for the GMO to come into contact with other related poxviruses.

 Poxviral recombination does not occur frequently in nature.

 even if HGT were to occur, expression of introduced genes is not expected to increase disease burden.



2.1 Increased disease burden to the GM virus

194.

Baseline information on the characteristics of Vaccinia virus is discussed in

Chapter 1Section 4. Briefly, VACV is not known to occur naturally in Australia. It was

previously used as a vaccine for smallpox, however vaccination was never mandatory in

Australia. Therefore, only a percentage of Australian residents, including those born and vaccinated overseas, would have had prior exposure to VACV. An even smaller percentage would retain significant immunity after three or more decades (Combadiere et al. 2004).

195.

VACV can be transmitted to people and animals by direct contact with the purified virus or with pustules that form on people infected with the virus, and by contact with items contaminated by contact with pustules (e.g. bandages, towels, sheets and clothing). The virus can persist for extended periods of time when in contact with organic material (e.g. pustular material or scabs).

196.

Trial participants will be intentionally exposed to the GM virus. However, a range of other people and animals may be inadvertently exposed – either directly to purified GMO supplied for use in the study, or to GM virus shed by trial participants.

197.

As unmodified VACV is available in Australia on a very limited basis and there is currently no disease burden due to this virus, any clinically significant symptoms in people, or disease in animals, due to infection with the GMO can be considered an increased disease burden.

198.

Pathways that could lead to an increased disease burden from the GM virus include:

 exposure of medical staff administering the GM virus, and other hospital staff or contractors handling it during preparation, transport, storage, disposal or analysis of patient samples;

 exposure of people to GM virus shed from trial participants who develop pustules. Such people could include clinical staff caring for participants on return visits to the hospital, other patients, home carers and close household contacts;

 exposure of animals such as domestic pets to GM virus shed from trial participants who develop pustules; and

 exposure of people or animals in the environment to GM virus disposed of via the general waste stream.

These pathways are discussed below.

2.1.1 Risk scenario 1 – Exposure of persons dispensing and administering the GMO

Risk source

GM virus

Causal pathway i.

Exposure of persons dispensing or administering the GMO in a hospital via:

 needle stick/sharps injury;

 contact with abraded skin or mucous membranes (esp. eyes)

 ii.


Potential harm

Clinical symptoms ranging from mild to severe (e.g. flulike illness, formation of pustules, severe adverse reactions)

Causal pathway

199.

Pharmacy or laboratory staff dispensing the GMO and medical staff administering it to trial participants could be exposed via a needle stick injury, a splash to the eyes or mouth, or through contact with contaminated items.



200.

The clinical trial will be conducted by appropriately qualified pharmacy and medical staff who have been specifically trained in the requirements of the study and appropriate

precautions (discussed in Chapter 13.1.5).

201.

Staff dispensing the GMO (i.e. diluting virus stock and loading syringes) will be required to handle the GMO in its most concentrated form, and could receive a high viral dose if exposed. They will work in a Class II biological safety cabinet, follow PC2 work practices and wear protective clothing that includes a laboratory gown, disposable gloves, eye protection and

surgical masks (see paragraphs 42 and 43). The use of protective clothing while handling

concentrated virus, plus the use of a biological safety cabinet and PC2 work practices minimise the likelihood of exposure. Eye protection and surgical masks will provide splash protection to the eyes and mouth while gloves will limit exposure via direct contact with the virus solution.

202.

Medical staff inoculating patients with the GMO will wear the same PPE, which would provide similar protection from exposure to the diluted virus solution.

203.

Sharps will be used while both dispensing and administering the GM virus (see

paragraph 38). Depending on equipment preferred at individual study sites, staff dispensing the

GMO may need to remove contaminated needles after loading diluted GMO solution into syringes. All sharps handling will follow institutional procedures, which would be in accordance with Universal Standard Precautions (World Health Organisation 2007a)and the

Australian Guidelines for the Prevention and Control of Infection in Healthcare (2010).

204.

Sharps will also be used for intratumoural injection (see paragraph 39), but the needle

will first be inserted into the patient, then the syringe attached via flexible tubing. The injection apparatus will be flushed with saline before the needle is withdrawn to minimise contamination of the injection site when the needle is withdrawn. Both procedures will minimise handling of contaminated sharps, and therefore the potential for exposure to the GMO via sharps injury.

Immediate disposal of needles into appropriate sharps containers will also minimise the risk of exposure by this route.

Potential harm

205.

Any dose received by accidental exposure to purified virus while dispensing or administering the GMO is likely to be far lower than the dose intentionally administered to trial participants (1x10

9

pfu).

206.

Even if exposure occurred, the GMO is likely to be attenuated in non-dividing cells and the site of exposure would not contain the density of rapidly dividing cells found in tumours. It is expected that viral replication would be limited in immune-competent people, and the GMO rapidly cleared by the immune system.

207.

Excluding at-risk individuals (including pregnant women, those with a severe inflammatory skin condition or a history of eczema, and the immunocompromised; see

paragraph 41) from handling or administering the GMO would minimise the possibility of a

severe adverse reaction. Should disease nonetheless eventuate, access to the available

treatments for some forms of severe VACV infection has been arranged (see Chapter 14.3.4).

208.

Neither the TK gene nor the introduced genes have previously been associated with toxicity or allergy in people or animals. hGM-CSF is of human origin, has not been modified, and there is no reason to think it would be toxic or allergenic when expressed in an infected cell. The lacZ gene and the



-galactosidase enzyme it encodes are widespread in the environment and have a long history of safe use in the laboratory. LacZ has also been expressed in vivo

in humans and animals without signs of toxicity (Chapter 15.2.3).

209.

hGM-CSF is a pro-inflammatory cytokine which can, in a concentration-dependent manner, stimulate localized inflammation or flu-like symptoms if present systemically. The



latter are similar to reported side effects of the GMO (paragraph 158), and dissipate once the

cytokine is removed. In low-risk individuals in whom viral replication is likely to be limited

(paragraph 206), it is expected that any production of hGM-CSF would be low level and

transient.

210.

Four inadvertent exposures (three needlesticks and one contact exposure) to the GMO have been documented in association with previous clinical trials and pre-clinical studies.

These did not cause clinical symptoms or require any treatment beyond immediate first aid and observation.

Conclusion

211.

Risk scenario 1 is not identified as a substantive risk because the potential for exposure would be minimised by standard handling procedures and specific precautions proposed by the applicant, the GMO is likely to be attenuated, at-risk people will be excluded from handling the

GMO and treatment for some adverse reactions is available in case of serious infection.

Therefore, this risk could not be greater than negligible and does not warrant further detailed assessment.

2.1.2 Risk Scenario 2 – Exposure of persons to GMO waste in clinical facilities

Risk source

GM virus

Causal pathway i.

Unused GMO or waste containing the GMO disposed of from clinical site

 ii.

Exposure of persons handling waste to the GMO

 iii.


Potential harm

Clinical symptoms ranging from mild to severe (e.g. flu-like illness, formation of pustules, severe adverse reactions)

Causal pathway

212.

Hospital staff (who may or may not be involved in the dealings) may come into contact with unused GMO or waste contaminated with the GM virus.

213.

All contaminated waste (including needles, syringes, tubing, gloves, swabs etc) will promptly be discarded into appropriately-labelled biological waste containers, which would minimise exposure to material contaminated with the GM virus once it has been discarded.

214.

Contaminated waste will be disposed of by each clinical site following standard clinical waste disposal methods (Australian Capital Territory 1991; 2011; 2012; EPA Victoria 2009;

New South Wales 1997; Northern Territory 2009; Queensland 2000; South Australia 2009;

Victoria 2000; West Australia 2004). The Industry Code of Practice for the Management of

Clinical and Related Wastes details requirements for clinical waste including waste segregation, packaging, labelling, storage, transport and accountability (Biohazard Waste

Industry Australia and New Zealand (BWI) 2010). The clinical waste stream typically involves destruction of infectious waste by incineration, autoclaving or chemical decontamination, which are considered appropriate for disposal of the GMO.

Potential harm

215.

As discussed in Risk Scenario 1, inadvertent exposure to the GMO is likely to involve a low dose, the GM virus is likely to be attenuated, and it is expected that any viral replication would be limited and the GMO rapidly cleared by the immune system. Low level expression of hGM-CSF and



-galactosidase have not previously been associated with adverse effects.



Finally, reported exposures to the GMO have not resulted in clinical symptoms or required specific treatment.

Conclusion

216.

Risk scenario 2 is not identified as a substantive risk because the potential for exposure would be minimised by discarding of contaminated waste into appropriate biological waste containers followed by disposal via the clinical waste stream, the GMO is likely to be attenuated and inadvertent exposure would involve small quantities only. Therefore, this risk could not be greater than negligible and does not warrant further detailed assessment.

2.1.3 Risk Scenario 3 – Exposure of people or animals to the GMO due to unintentional release during transport or storage

Risk source

GM virus

Causal pathway i.

Exposure of people or animals to the GM virus due to unintentional release during transport or storage

 ii.


Potential harm


Causal pathway

217.

Staff at clinical or storage sites (who may or may not be involved in the dealings), and people or animals outside of these sites, may come into contact with the GMO due to a spill during transport or storage.

218.

As described in Chapter 13.1.4, the GM virus will be supplied in small volumes and

securely packaged in sealed vials (the primary container), individually packaged in labelled cardboard boxes (the clinical product pack), and sealed for transport within leak-proof secondary packaging (a plastic bag).

219.

Transport for the purpose of import and distribution within Australia will be by commercial courier companies experienced in the transport of pharmaceutical products, and in accordance with IATA Dangerous Goods Regulations and, within Australia, the Australian

Dangerous Goods Code .

220.

For transport within clinical sites, the GMO will be double-contained in accordance with the Regulator’s Guidelines for the Transport, Storage and Disposal of GMOs .

221.

Storage at the central depot and clinical sites will be in the primary packaging supplied, with a secure freezer providing secondary containment. Access will be restricted to staff working in the pharmacy/laboratory or storage facility, the vial and box label will clearly indicate the contents, the product will be stored only with other therapeutic agents and not with laboratory samples, and it will be dispensed only with written authorization from the lead investigator at the site.

222.

Any spills occurring in a clinical setting would be disinfected and cleaned in accordance with the Australian Guidelines for the Prevention and Control of Infection in Healthcare

(2010). Spills outside of clinical facilities would be disinfected and contained according to the requirements of the Regulator’s


In addition, the GMO is supplied as purified virus particles which have reduced capacity to survive in the environment compared with VACV derived from patients and found in scabs

and other biological specimens (Chapter 14.10). Therefore there is little potential for exposure

of humans or other animals to the GMO.



223.

When the study at each clinical site is complete, any unused GMO will be destroyed or returned to the trial sponsor. Records of all GMO received, dispensed and destroyed will be maintained and verified during regular site visits by the CRO and licence holder.

Potential harm

224.

As discussed in Risk Scenario 1, inadvertent exposure to the GMO is likely to involve a low dose, the GM virus is likely to be attenuated, and it is expected that any viral replication would be limited and the GMO rapidly cleared by the immune system of people or animals.

Low level expression of hGM-CSF and



-galactosidase have not previously been associated with adverse effects. Finally, reported exposures of people to the GMO have not resulted in clinical symptoms or required specific treatment.

Conclusion

225.

Risk scenario 3 is not identified as a substantive risk because the potential for exposure would be minimised by appropriate packaging and containment during transport and storage, ensuring spills procedures are in place, and disposing of unused GMO at the end of the study.

In addition, the GMO is likely to be attenuated and inadvertent exposure would involve small quantities only. Therefore, this risk could not be greater than negligible and does not warrant further detailed assessment.

2.1.4 Risk Scenario 4 – Exposure of persons analysing patient samples that contain the GMO

Risk source

GM virus

Causal pathway i.


 ii.

Samples containing GMO collected from trial participant

 iii.

Laboratory staff exposed to GMO during analysis iv.




Potential harm

Clinical symptoms ranging from mild to severe (e.g. flu-like illness, formation of pustules, severe adverse reactions).

Causal pathway

226.

Blood and tissue specimens collected from patients will routinely be exported for analysis overseas, but could if required be analysed in Australia. Such samples may contain low levels of the GMO (Hwang, 2011; Park, 2008). Laboratory staff in Australian facilities could be exposed by contact with abraded skin, eyes or mouth.

227.

The applicant has advised that analytical laboratory staff would follow institutional

Standard Operating Procedures in place for the safe handling and disposal of clinical and diagnostic specimens.

The National Pathology Accreditation Advisory Council (NPAAC) plays a key role in ensuring the quality of Australian pathology services and is responsible for the development and maintenance of standards and guidelines for pathology practices. The standards include safety precautions to protect the safety of workers from exposure to infectious microorganisms in pathology laboratories . Australian pathology laboratories conform to AS/NZS 2243.3:2010 Safety in Laboratories Part 3: Microbiological Safety and

Containment , which stipulates that human clinical and diagnostic specimens be handled in PC2 containment as a minimum standard. As unmodified VACV is classified as a Risk Group 2 organism in Australia, this would provide sufficient protection from exposure to the GM virus.



Potential harm

228.

As discussed in Risk Scenario 1, inadvertent exposure to the GMO is likely to involve a low dose, the GM virus is likely to be attenuated, and it is expected that any viral replication would be limited and the GMO rapidly cleared by the immune system. Low level expression of hGM-CSF and



-galactosidase have not previously been associated with adverse effects.

Finally, reported exposures to the GMO have not resulted in clinical symptoms or required specific treatment.

Conclusion

229.

Risk scenario 4 is not identified as a substantive risk because the potential for exposure would be minimised by handling the GMO according to national standards that require PC2 containment and PC2 work practices. In addition, the GMO is likely to be attenuated and inadvertent exposure would involve small quantities only. Therefore, this risk could not be greater than negligible and does not warrant further detailed assessment.

2.1.5 Risk Scenario 5 – Exposure of nursing staff and other patients to the GMO

Risk source

GM virus

Causal pathway i.


 ii.


 iii.

Exposure of hospital staff or other patients to trial participant shedding the GMO

 iv.


Potential harm


Causal pathway

230.

Patients inoculated with the GMO will be required to return to the hospital for additional treatment and follow-up tests. Patients inoculated by the intratumoral route have been found to shed virus only via pustular lesions that sometimes develop after the first round of treatment

(Chapter 15.3.6). Should a patient develop GMO-related lesions, clinical staff caring for them

or collecting samples, and other hospital patients, could be exposed to GMO shed by the participant.

231.

Trial participants who develop lesions will be required to follow well-established hygiene practices known to minimise interpersonal transmission of the virus (see paragraphs

27 and 28). These practices will be explained to prospective participants during initial

screening and anyone unwilling or unable to comply will not be enrolled.

232.

Care of and samples collection from inoculated patients will be in accordance with

Universal Standard Precautions at a minimum (see paragraph 44). Where returning patients

present with GMO-related lesions, additional risk-based ‘Contact Precautions’ are

recommended (see paragraph 45) to minimise opportunities for transmission to staff and other

patients. It should be noted that two inadvertent exposures have been documented in association with previous clinical trials

8

. Provided suitable precautions, based on risk

8 Four exposures (three needlesticks and one contact exposure) have been documented by the international trial sponsor. Two of these occurred in the course of clinical trials that have involved approximately 1200 patient


Office of the Gene Technology Regulator assessment and documented in Standard Operating Procedures (SOPs) are in place and followed at each study site, exposure of clinical staff and other patients to the GMO should be minimised.

Potential harm

233.

As discussed in Risk Scenario 1, the GM virus is likely to be attenuated, and it is expected that any viral replication would be limited and the GMO rapidly cleared by the immune system. Low level expression of hGM-CSF and



-galactosidase have not previously been associated with adverse effects. Finally, reported exposures to the GMO have not resulted

in clinical symptoms or required specific treatment (see paragraphs 205-206 and 208-210.

234.

The applicant has proposed to exclude at-risk individuals (including pregnant women, those with a severe inflammatory skin condition or a history of eczema, and the

immunocompromised; see paragraph 41) from caring for patient with pustules or sharing a

hospital room with them, which would minimise the possibility of a severe adverse reaction in an exposed person. Should disease nonetheless eventuate, access to the available treatments for

some forms of severe VACV infection has been arranged (see Chapter 14.3.4).

Conclusion

235.

Risk scenario 5 is not identified as a substantive risk because the potential for exposure would be minimised by implementing risk-based precautions at each clinical site and requiring that trial participants who develop pustules follow clearly-defined hygiene practices, the GMO is likely to be attenuated, at-risk people will be excluded from caring for patients with pustules or sharing a hospital room with them, and treatment for some adverse reactions is available in case of serious infection. Therefore, this risk could not be greater than negligible and does not warrant further detailed assessment.

2.1.6 Risk Scenario 6 – Exposure of people or animals in the home environment to the

GMO

Risk source

GM virus

Causal pathway i.

ii.

iii.

iv.







Exposure of people (e.g. carers or household contacts), other than at-risk people, or animals (e.g. domestic pets), through contact with trial participant or contaminated items (e.g. contaminated dressings) outside the clinical/hospital setting.




Potential harm


Causal pathway

236.

Patients inoculated with the GMO will reside in their homes over the course of the trial.

Should they develop GMO-related pustules after the first round of treatment, household inoculations (or one exposure per 600 inoculations). The proposed trial in Australia will involve up to 150 patient inoculations.


Office of the Gene Technology Regulator contacts such as carers or family members, and animals such as domestic pets, could be exposed to the GM virus.

237.

A wide range of animal species are susceptible to infection with VACV, although information about development of clinical disease in species other than cattle, mice and rabbits is limited. Household pets are most likely to be exposed, directly or indirectly, to GMO shed by trial participants. Dogs and cats – the most common domestic pets in Australia – can both

be infected with VACV (Chapter 14.2).

238.

Trial participants who develop pustules will be instructed to follow well-established

hygiene practices known to minimise interpersonal transmission of VACV (see paragraphs 27 and 28). These practices will be explained to prospective participants during initial screening

and anyone unwilling or unable to comply will not be enrolled. Participants will also be expected to seal contaminated disposable items in a primary container (e.g zip-loc bag) before placing in the household waste. They will be instructed to launder contaminated fabrics in hot

water with detergent (see paragraph 48).

239.

These measures are consistent with those recommended to reduce transmission of wildtype VACV after vaccination by the United States Centre for Disease Control (CDC) Advisory

Committee on Immunization Practices, and would limit the opportunity for household contacts to come into contact with shed GMO.

240.

The applicant has not specifically addressed the issue of contact with household pets.

However, the measures proposed to minimise transmission to close human contacts should also minimise transmission to animal contacts, provided they are applied with equal attention.

Potential harm

241.

As discussed in Risk Scenario 1, the GM virus is likely to be attenuated, and it is expected that any viral replication would be limited and the GMO rapidly cleared by the immune system. Low level expression of hGM-CSF and



-galactosidase have not previously

been associated with adverse effects (see paragraphs 205-206 and 208-210.

242.

With similar practices in place, the applicant has advised that no discernible transmission to non-participants has been reported in previous clinical trials, involving over 300 patients and

1200 inoculations with the GM virus.

Conclusion

243.

Risk scenario 6 is not identified as a substantive risk because the potential for exposure would be minimised by ensuring that trial participants who develop pustules are willing and able to comply with well-established hygiene practices, seal contaminated waste in a primary container before placing with household waste, and correctly laundering contaminated textiles.

The GMO is also likely to be attenuated, no previous transmission events have been reported, and treatment for some adverse reactions is available in case of serious infection. Therefore, this risk could not be greater than negligible and does not warrant further detailed assessment.

2.2 Horizontal transfer of genes or genetic elements to other organisms

244.

Horizontal gene transfer (HGT) is the stable transfer of genetic material from one organism to another without reproduction (Keese 2008). All genes within an organism, including those introduced by gene technology, are capable of being transferred to another organism by HGT. HGT itself is not considered an adverse effect, but an event that may or may not lead to harm. A gene transferred through HGT could confer a novel trait to the recipient organism through expression of the gene itself or through changes in expression of endogenous genes. The novel trait may result in negative, neutral or positive effects.



245.

Information on the presence of the introduced genes in the environment is provided in

Sections 5.4 and 5.5. They are derived from humans and bacteria ( E. coli ) and are already available for HGT from these natural sources. Thus their transfer to organisms beyond other viruses will not be assessed further, and the risk assessment will address potential HGT only between the GMO and other viruses.

2.2.1 Risk Scenario 9 – Presence of the introduced genetic material in other organisms as a result of horizontal gene transfer

Risk source

GM virus

Causal pathway i.

Exposure of people or animals to the GM virus leading to infection (see risk Scenarios 1-8)

 ii.

Person or animal also infected with another compatible virus

 iii.

Both viruses infect and replicate in the same host cell

 iv.

Recombination between viral genomes takes place

 v.

Recombinant virus infects other hosts

Potential harm

Disease in humans or animals.

Establishment of a novel virus in the environment.

Causal pathway

246.

Recombination between two viruses may occur if they simultaneously infect the same cell. Recombination can occur within and between viral types (DeFillipis & Villarreal 2001), meaning that introduced genes could potentially be transferred to other viruses. While recombination between different classes of virus can occur, its frequency decreases with decreasing relationship between viruses – meaning that the GM virus is more likely to recombine with another poxvirus than with an unrelated virus.

247.

There is no reservoir of vaccinia virus in the Australian environment that would allow recombination between GM and wild-type VACV. Other uncharacterised poxviruses are found in Australian wildlife; their prevalence is unknown but wildlife is unlikely to come into contact with trial participants. Contact between scavenging animals and participants’ discarded waste is discussed further in Section 3.2.2 and considered highly unlikely due to dilution within the general waste stream.

248.

Should people or animals be infected with two different poxviruses, the same cell would need to be infected for there to be any potential for recombination. The GM virus is expected to be attenuated with respect to its ability to replicate efficiently in non-dividing cells.

Furthermore, poxviral recombination does not occur readily. Physical constraints around the replication and assembly processes limit the mixing of viral genomes (see Chapter 1,

Section 4.8), and few examples have been documented.

Potential harm

249.

A key consideration in the risk assessment process should be the safety of the protein product resulting from expression of the introduced genes rather than horizontal gene transfer per se (Keese 2008). If the introduced genes or their end products are not associated with harm to people or other organisms then even in the unlikely event of HGT occurring, they should not pose risks to humans, animals or the environment. The introduced genes are derived from humans and bacteria ( E. coli ) and have not been associated with toxic effects. They are not expected to provide any advantage to a receiving virus, nor cause adverse effects in a host organism.



Conclusion

250.

The potential for an adverse outcome as a result of horizontal gene transfer is not identified as a substantive risk. Therefore, this risk could not be greater than negligible and does not warrant further detailed assessment.

Section 3 Risk characterisation

251.

Nine risk scenarios were postulated and evaluated. They are summarised in Table 3, where circumstances that share a number of common features are grouped together in broader risk categories. In the context of control measures proposed by the applicant, two of the risk scenarios were identified as posing substantive risks which warranted further assessment. More detail on the evaluation of these scenarios is provided in Section 3 of this chapter.

3.1 Risk Scenario 7 – Exposure of at-risk people in the home environment to GM virus shed by trial participants

Risk source

GM virus

Causal pathway i.


 ii.

Trial participant develops pustular lesions and sheds the

GMO

 iii.

Exposure of at-risk people (such as pregnant women, those with a severe inflammatory skin condition or a history of eczema, and the immunocompromised; e.g. carers or household contacts) through contact with trial participant or contaminated items (e.g. contaminated dressings) outside the clinical/hospital setting

 iv.


Potential harm

Marginal to severe clinical symptoms.

252.

Once patients return home after treatment, home carers and close contacts (e.g. partners and other family members) could be exposed if patients shed the GM virus. Certain individuals are likely to suffer more severe responses to the GM virus than the general population.

3.1.1 Likelihood assessment

253.

The extent to which trial participants shed the GMO is an important factor in assessing

its potential for transmission. As discussed in Chapter 15.3.5, patients inoculated by the

intratumoral route have been found to shed virus only via pustular lesions that sometimes develop. Lesions have typically formed within 3-7 days of the first treatment cycle (but not subsequent cycles), and in diverse locations including the soles, palms, arms, fingers, torso, face, oral mucosa and lips (Breitbach, 2011; Cripe, 2015; Heo, 2013; Park, 2015). While they have occurred inconsistently, a recent publication reported lesions in 100% of patients (3/3) receiving a GMO dose comparable to that proposed for this study (Cripe, 2015). The potential therefore exists for any or all of the trial participants to develop pustules. The number of lesions, however, is usually small (1-10).

254.

Any trial participants who develop lesions will be required to follow well-established hygiene practices known to minimise interpersonal transmission of the virus (see paragraphs

27 and 28). These practices will be explained to prospective participants during initial

screening and anyone unwilling or unable to comply will not be enrolled in the trial.

Participants will also be instructed to launder contaminated textiles in hot water with detergent and seal contaminated disposable items in a primary container (e.g. a zip-lock bag) before

placing in the household waste (see paragraph 47).



255.

These measures are consistent with those recommended to reduce transmission of unmodified VACV after vaccination by the United States Centre for Disease Control (CDC)

Advisory Committee on Immunization Practices, and would limit the opportunity for household contacts to come into contact with the GMO.

256.

Participants will also be instructed that, should they develop a pustule, they must avoid direct physical contact with ‘Excluded Individuals’, who are at highest risk of developing

severe disease (paragraph 28 (e)). Again, prospective participants unable or unwilling to

comply will not be enrolled in the trial.

257.

Given that lesions are initially small and do not form in a consistent location (such as the inoculation site), there is potential for patients to be unaware of a lesion in its early stages.

These lesions have previously developed within 3-7 days of the initial treatment, and no follow up visits to the hospital – when the patient could be assessed – are scheduled within this time

frame. Viral shedding reportedly occurs from the papule stage (Chapter 14.4). It is possible

therefore, that Excluded Individuals among a patient’s close associates could be exposed to the

GMO before the patient is aware that they should avoid physical contact with that person.

258.

This scenario is considered highly unlikely to occur as the number of lesions and quantity of virus shed at an early stage would be low, patients would be following established hygiene practices and the at-risk person would need to be exposed to the GM virus in a manner that leads to infection. Historically, reports of interpersonal transmission have been infrequent

(Chapter 14.4).

3.1.2 Consequence assessment

259.

The effect of the GM virus on at-risk individuals is unknown as exposure of such individuals has not been reported. The consequences of infection may be less severe than those

described for unmodified VACV in Chapter 14.3.3 due to the expected effect of the genetic

modification, restricting viral replication.

260.

Experience with the Raboral V-RG

®

rabies vaccine discussed in Chapter 15.2.1 has,

however, shown that inadvertent exposure to a modified VACV possessing a disrupted TK gene can cause illness in at-risk individuals, which has required hospitalisation and specialised

treatment (paragraph 130). Information about the total number of exposures is limited to a

single vaccination program (Ohio 1990 – 2000) (Rupprecht et al. 2001) but in this example, one of the two contraindicated (at-risk) people exposed to the vaccine suffered an adverse reaction.

261.

The Raboral V-RG

®

rabies vaccine is derived from the Copenhagen vaccinia strain.

Historically, the NYCBH vaccinia ‘strain’, as used in the Dryvax

®

vaccine on which the GMO is based, was associated with a lower rate of adverse reactions than other vaccine strains

(including Copenhagen) (Kretzschmar et al. 2006). Therefore, the GM VACV proposed for trial in this application, JX-594, may produce less severe adverse reactions in at-risk people than Raboral V-RG

®

. However, the Dryvax

®

vaccine preparation is a heterogenous pool of vaccinia strains which are known to vary in virulence (Osborne et al. 2007; Li et al. 2006;

Nalca & Zumbrun 2010; Qin et al. 2011). The GMO is derived from a single VACV clone from this pool, isolated by plaque purification after carrying out the genetic modification. This clone has not been characterised and so its unique properties are not known. It may be more or less virulent than the phenotypic ‘average’ displayed by the Dryvax

®

preparation as a whole.

262.

Given the uncertainty regarding the ability of the GMO to induce an adverse reaction in at-risk people, the potential harm to this group may therefore be considered marginal (minimal or no increase in illness/injury to people) to intermediate (significant increase in illness/injury to people that requires specialised treatment).



3.1.3 Risk estimate

263.

The risk estimate is based on a combination of the likelihood and consequence

assessments, using the Risk Estimate Matrix (see Chapter 2, Section 1), as described in the

Regulator’s Risk Analysis Framework (OGTR 2013).

264.

The consequences of exposure via this pathway and infection with the GMO are considered marginal to intermediate but highly unlikely to occur. The risk is therefore estimated to be negligible (risk is of no discernible concern and there is no present need to invoke actions for mitigation) to low (risk is of minimal concern, but may invoke actions for mitigation beyond standard practices). Consideration of the need for treatment of this low risk is made in Section 5, below.

3.2 Risk Scenario 8 – Exposure of people or animals to GM virus following disposal of GM waste into landfill

Risk source

GM virus

Causal pathway i.


 ii.

Trial participant develops pustular lesions and sheds the

GMO.

 iii.

Material (e.g. used dressing) contaminated with the GM virus enters general waste.

 iv.

Exposure of people or animals in the environment to contaminated material. v.

Establishment of infection.



Potential harm

Clinical symptoms in people or animals.

Secondary transmission.

265.

The applicant has proposed that trial participants who develop viral lesions dispose of used dressings and other contaminated items via the general waste stream into landfill.

Participants would be instructed to seal such items in a primary container (e.g. a zip-lock

plastic bag) before discarding (see paragraph 48).

266.

This disposal method is consistent with that recommended by the United States CDC

Advisory Committee on Immunization Practices in the context of vaccination with wild-type

VACV. It also appears in the Australian Department of Health Guidelines for Smallpox

Outbreak, Preparedness, Response and Management . However, these guidelines focus on minimising inadvertent transmission of VACV to people such as other household members, rather than environmental spread.

267.

This practice would minimise exposure of household contacts (both human and animal), and risks to these groups were considered in Risk Scenarios 6 and 7. However, other people or animals could be exposed to the GMO through contact with contaminated items after they enter the general waste stream, as the primary barrier may not remain intact after handling, compaction and spreading of waste.

268.

Furthermore, unmodified VACV is used for vaccination in Australia on a very limited basis and is not known to be present in the environment. Although environmental persistence of VACV has rarely occurred in 150 years of smallpox vaccination, it is well-documented in

Brazil (Chapter 14.2) and it is not known how or why it established in the environment in that

country.

3.2.1 Likelihood assessment

269.

Rubbish at landfill sites is typically compacted by heavy vehicles and eventually covered by other waste, so would be exposed and accessible for a limited (but unknown) period.



270.

The amount of pustular waste likely to be disposed of at any one landfill site is limited, as a maximum of 50 patients are proposed to be enrolled in the trial, spread across five states of

Australia and a number of different local government areas.

271.

However, the quantity of waste generated at patients’ homes could be significant relative to that generated at study sites. Lesions observed in previous clinical trials, while few in number, have taken up to six weeks to heal (Heo et al. 2013; Park et al. 2015), dressings would be contaminated with virus, and frequent (up to daily) changing of the dressings will be required.

272.

Poxviruses are known for their ability to persist in the environment (Chapter 14.10).

Virus present in pustular waste, being both derived from patients and associated with organic

matter, are in what is reportedly the most stable form (Chapter 14.10). It is reasonable to expect

that the GMO could remain viable for the time it remains accessible at a landfill site.

273.

As landfill operators manipulate material dumped at landfill sites, e.g. dumping, compacting and spreading the waste, there is some opportunity for exposure of people.

Relevant routes of exposure would be via contact with skin or mucous membranes.

274.

Wild or feral animals and birds could also contact waste contaminated with the GMO.

VACV has a broad host range that includes many animal species and potentially birds

(Chapter 14.2). In the event that animals or birds foraging in landfill sites come into contact

with viable GM virus, exposure would most likely be by the oral route. Studies with the

VACV-based rabies vaccine (Raboral V-RG

®

) discussed in Chapter 15.2.1 found that oral

exposure can lead to infection. Infection may also occur through contact with other mucosa or damaged skin.

275.

This scenario is considered possible, but given the low quantity of waste entering waste management sites and subsequent dilution in landfill, contact of waste carrying the GMO with people or animals is highly unlikely .

3.2.2 Consequence assessment

276.

In the event that people are exposed to the GMO, the potential harms are as discussed previously. The consequences for at-risk people were assessed as marginal to intermediate

(see subsection 3.1.2, above). For other people, inadvertent exposure to the GMO is likely to involve a low dose, and it is expected that any viral replication would be limited and the GMO rapidly cleared by the immune system. Low levels of hGM-CSF and



-galactosidase have not

previously been associated with adverse effects (see paragraphs 205-206 and 208-210). For

these people the consequences would be marginal (minimal or no increase in illness/injury to people) to minor (minor increase in illness/injury to people that is readily treatable).

277.

Safety studies with the VACV-based rabies vaccine (Raboral V-RG

®

) discussed in

Chapter 15.2.1 found that oral exposure led to low level viral replication in the mouth and

throat of animals but no clinical signs or viral spread to other organs. Studies in target species also demonstrated a lack of pathogenicity when the recombinant VACV was administered by a

variety of other routes (see paragraphs 127 and 128). Expression of hGM-CSF by the GMO

under consideration could lead to additional symptoms, however available data suggests it is

inactive in many animal species (paragraph 134). The consequence for animals is therefore

considered marginal .

278.

In the event that infection of an animal does occur, very little horizontal transmission

from animals vaccinated with Raboral V-RG® was observed (paragraph 129), suggesting that

secondary transmission and persistence in the environment are not likely to occur. However, as

noted above (paragraph 268), it is not known how unmodified VACV entered the environment

in Brazil.



279.

Overall, the consequence for animals is therefore considered marginal (minimal or no increase in harm to desirable components of the environment).

3.1.2.3 Risk Estimate

280.

The risk estimate is based on a combination of the likelihood and consequence

assessments, using the Risk Estimate Matrix (see Chapter 2, Section 1), as described in the

Regulator’s Risk Analysis Framework (OGTR 2013).

281.

For people not at risk of serious adverse reactions to VACV infection, and animals in the environment, the consequences of exposure are no greater than minor , and are highly unlikely to occur. The risk is therefore estimated to be negligible (risk is of no discernible concern and there is no present need to invoke actions for mitigation).

282.

For people who do fall into an at-risk group (including pregnant women, those with a severe inflammatory skin condition or a history of eczema, and the immunocompromised; see

paragraph 25), exposure to and infection with the GMO via this pathway is considered to be

marginal to intermediate in consequence but to be highly unlikely to occur. The risk is therefore estimated to be negligible (risk is of no discernible concern and there is no present need to invoke actions for mitigation) to low (risk is of minimal concern, but may invoke actions for mitigation beyond standard practices). Consideration of the need for treatment of this low risk is made in Section 5, below.

Section 4 Uncertainty

283.

Uncertainty is an intrinsic part of risk analysis

9

. There can be uncertainty about identifying the risk source, the causal linkage to harm, the type and degree of harm, the chance of harm occurring or the level of risk. In relation to risk management, there can be uncertainty about the effectiveness, efficiency and practicality of controls.

284.

For clinical trials, which involve research, some knowledge gaps are inevitable. This is one reason they are conducted under specific limits and controls intended to minimise exposure to the GMO and thus decrease the likelihood of harm.

285.

For DIR 140, uncertainty is noted particularly in relation to the degree of attenuation of the GMO relative to unmodified VACV, and its likely effect on at-risk people.

286.

There is little data comparing the GMO with the parent organism on which to base a robust assessment of its attenuation. There is also little information about its behaviour in people with normal levels of dividing cells (i.e. people who do not have cancer). Therefore information on unmodified vaccinia viruses and other vaccinia virus strains modified using a similar TK -disruption strategy were used in the risk assessment.

287.

The uncertainty about the GMO’s ability to cause adverse reactions in at-risk people has been addressed in Scenarios 7 and 8 by considering a range of possible consequences should such individuals be exposed to the GM virus. Accommodating this uncertainty resulted in an estimate of risk of negligible to low.

Section 5 Risk Evaluation

288.

Risk is evaluated against the objective of protecting the health and safety of people and the environment to determine the level of concern and, subsequently, the need for controls to

9 A more detailed discussion is contained in the Regulator’s Risk Analysis Framework available from the OGTR website or via Free call 1800 181 030.


Office of the Gene Technology Regulator mitigate or reduce risk. Risk evaluation may also aid consideration of whether the proposed dealings should be authorised, need further assessment, or whether additional information is needed.

289.

Factors used to determine which risks need treatment may include:

 risk criteria

 level of risk

 uncertainty associated with risk characterisation

 interactions between substantive risks.

290.

Nine risk scenarios were postulated whereby the proposed dealings could give rise to harm to people or the environment. This included consideration of the potential for: expression of the introduced genes and genetic modifications to impact on the disease burden caused by the GM virus; infection of at-risk individuals; infection of animals; and establishment of the

GM virus in the environment. The opportunity for gene transfer to other organisms, and its effects if it were to occur, was also considered.

291.

A risk is only identified as substantive when a risk scenario is considered to have some chance of causing harm. Risk scenarios that do not lead to harm, or could not reasonably occur, do not represent an identified risk and do not advance any further in the risk assessment process. In the context of the control measures proposed by the applicant, two of the nine risk scenarios were identified as substantive risks that required further assessment.

292.

The likelihood and consequences of the two substantive risks were characterised

(Chapter 2, Section 3), and the level of risk estimated using the Risk Estimate Matrix, as described in the Regulator’s Risk Analysis Framework (OGTR 2013) (see Chapter 2,

Section 1).

293.

The risk from exposure of at-risk individuals through contact with trial participants who are shedding the GMO was estimated as posing negligible to low risks to human health and safety. The risk from exposure of at-risk individuals to the GM virus following disposal of

GMO-contaminated material into general waste by trial participants was also estimated as posing negligible to low risks to human health and safety.

294.

The applicant has proposed some control measures related to these risks. It is proposed treatment measures be considered to mitigate each of the identified negligible to low risks.

Treatment measures to manage these risks are considered in Chapter 3.

295.

Given that the two substantive risks are assessed as negligible to low, the Regulator considers that the dealings involved in this proposed release do not pose a significant risk to either people or the environment 10 .

10 As none of the proposed dealings are considered to pose a significant risk to people or the environment, section

52(2)(d)(ii) of the Act mandates a minimum period of 30 days for consultation on the RARMP. However, the

Regulator has allowed 6 weeks for the receipt of submissions from prescribed experts, agencies and authorities, and the public.



Chapter 3 Risk management

Section 1 Background

296.

Risk management is used to protect the health and safety of people and to protect the environment by controlling or mitigating risk. The risk management plan addresses risks evaluated as requiring treatment, evaluates controls and limits proposed by the applicant, and considers general risk management measures. The risk management plan informs the

Regulator’s decision-making process and is given effect through licence conditions.

297.

Under section 56 of the Act, the Regulator must not issue a licence unless satisfied that any risks posed by the dealings proposed to be authorised by the licence are able to be managed in a way that protects the health and safety of people and the environment.

298.

All licences are subject to three conditions prescribed in the Act. Section 63 of the Act requires that each licence holder inform relevant people of their obligations under the licence.

The other statutory conditions allow the Regulator to maintain oversight of licensed dealings: section 64 requires the licence holder to provide access to premises to OGTR inspectors and section 65 requires the licence holder to report any information about risks or unintended effects of the dealing to the Regulator on becoming aware of them. Matters related to the ongoing suitability of the licence holder are also required to be reported to the Regulator.

299.

The licence is also subject to any conditions imposed by the Regulator. Examples of the matters to which conditions may relate are listed in section 62 of the Act. Licence conditions can be imposed to limit and control the scope of the dealings and to manage risk to people or the environment. In addition, the Regulator has extensive powers to monitor compliance with licence conditions under section 152 of the Act.

300.

Licence conditions are discussed and summarised in this Chapter and listed in detail in

Chapter 4 (the draft licence).

Section 2 Risk treatment measures for substantive risks evaluated as requiring treatment

301.

The risk identification process (Chapter 2Section 2) led to identification of two

substantive risks. These risks, relating to exposure of at-risk individuals to GM virus shed by trial participants outside the clinical setting and disposal of GM waste via the general waste stream, were characterised in Chapter 2, Section 3. Risk evaluation proposed that each of these risks should be treated.

302.

The applicant has proposed that patients who have GMO-related lesions avoid contact with at-risk people but has not proposed measures to minimise the potential for exposure due to unrecognised GMO-related lesions. The risk posed by transmission to at-risk individuals from an unrecognised lesion was assessed as negligible to low. To manage this risk, the licence holder could instruct all trial participants to avoid direct physical contact with individuals at risk of severe adverse reactions to VACV (including pregnant women, those with a severe inflammatory skin condition or a history of eczema, and the immunocompromised) after the first round of treatment with the GMO until the first follow-up visit to the clinic that takes place on or after day 8 post-inoculation. During the follow-up visit, the presence or absence of

GMO-related lesions should be assessed. This treatment measure is considered to be practical and effective and has been included as a draft licence condition.

303.

The applicant has proposed that trial participants dispose of dressings, which may be contaminated with the GMO, by sealing them in a container or plastic bag and disposing of it in general waste. The risk posed by transmission to at-risk individuals from disposal of pustular waste via the general waste stream was assessed as negligible to low. To manage this risk,

Chapter 3 – Risk management 51

Office of the Gene Technology Regulator patients could return waste generated during home-care of GMO-related lesions to the treating hospital for disposal via the clinical waste stream. To do this without introducing additional risk, trial participants should seal all such contaminated waste inside suitable primary containers (e.g. sealable plastic bags) as proposed by the applicant and place these within a sealable secondary container. The applicant could provide trial participants with a secondary container appropriate for transporting the waste back to the hospital, and labelled in accordance with the Regulator’s guidelines for the Transport, Storage and Disposal of GMOs . Between visits to the hospital, the trial participant should store the waste such that it is inaccessible to children and animals. These treatment measures are considered to be practical and effective.

Draft licence conditions have been included that require to licence holder to provide trial participants with appropriate waste containers and instruction in handling, storing and returning waste.

2.1 Summary of draft licence conditions proposed to manage identified risks

304.

Licence conditions have been proposed to reduce the potential for transmission of the

GMO from trial participants to at-risk individuals. These include requirements that:

 all trial participants be instructed to avoid direct physical contact with at-risk individuals for at least 7 days after the first round of treatment with the GMO, and until the presence or absence of GMO-related lesions has been assessed by their clinician.

 ensure all contaminated waste generated during home care of GMO-related lesions is returned to the treating hospital for disposal via the clinical waste stream.

Section 3 General risk management

305.

The limits and controls proposed in the application were important in establishing the context for the risk assessment and in reaching the conclusion about the risks posed to people and the environment. Therefore, to maintain the risk context, licence conditions have been drafted to limit the release to the proposed scale and duration, and to restrict the spread and persistence of the GMO and its genetic material in the environment.

3.1 Consideration of the limits and controls proposed by Clinical Network

Services Pty Ltd

306.

Chapter 1, Sections 2.2 and 2.3 provide details of the limits and controls proposed by

CNS, which are discussed in the risk scenarios considered in Chapter 2. The appropriateness of these limits and controls is considered further below.

307.

The proposed clinical trial will involve a maximum of 50 participants within Australia, and most activities will take place in hospitals providing specialised cancer-treatment services.

The applicant has proposed to complete the trial within five years of commencement. These limits would limit the exposure of people and animals to the GM viruses. To provide some flexibility in patient enrolment, draft licence conditions allow for administration of the GMO in hospitals providing specialised cancer-treatment services to up to75 participants, over a 5 year period.

308.

Excluding individuals at risk of severe adverse effects from exposure to the GM virus from participating in the trial, and from handling the GM virus and caring for patients who present with GMO-related lesions, would reduce the possibility of complications requiring medical treatment and excessive shedding of the GMO into the environment. These include people who have previously experienced an adverse reaction to VACV vaccination (excluded from trial participation only, not from handling the GMO or caring for patients in the hospital setting), people with immunodeficiencies, people with inflammatory skin conditions or a


Office of the Gene Technology Regulator history of eczema, and women who are pregnant or breastfeeding. These exclusion criteria have been included as draft licence conditions.

309.

The GMO will be administered by intratumoural inoculation. This route is associated

with reduced viral shedding comparing with intravenous infusion (see Chapter 15.3.6), so

would limit the opportunity for interpersonal transmission of the GMO and has been included as a draft licence condition.

310.

Participants will be inoculated and cared for by trained clinical staff at hospital facilities in accordance with the World Health Organisation Standard Precautions in Health Care

(World Health Organisation 2007b) and the International Conference on Harmonisation Good

Clinical Practice Guidelines (ICH 1996). The WHO standard precautions detail appropriate hygiene, personal protective equipment and decontamination procedures to prevent direct contact with infectious agents. These practices would minimise exposure of people handling the GMO and caring for patients. The draft conditions require administration in hospitals providing specialised cancer-treatment services and adherence to ICH-GCP and TGA GCP

Guidelines and WHO Universal Standard Precautions.

311.

When handling the GMO, the applicant has indicated that PPE including a gown, gloves, eye protection and a surgical mask must be worn. Additionally, while dispensing the GMO, a

Class II biological safety cabinet (BSC) and PC2 work practices would be used. These practices would further reduce exposure of people handling the GMO, and have been included as draft licence conditions.

312.

As patients returning to the hospital for further treatment or follow-up may present with

GMO-related lesions, the applicant has proposed that clinical sites conduct a risk assessment and develop ‘Contact Precautions’ appropriate to their facility that minimise the possibility of

GMO transmission to clinical staff and other patients, including patients in at-risk categories.

Such precautions would further reduce the risk of exposure of clinical staff and patients to the

GMO. Draft licence conditions require the licence holder to ensure that suitable precautions are developed through risk assessment, documented in Standard Operating Procedures (SOPs) and implemented at each study site.

313.

The applicant will require trial participants to take precautions intended to minimise interpersonal spread of the GMO, which would reduce the opportunity for exposure of other people to the GMO or shedding of the GMO into the environment. These measures include covering pustules, wearing a surgical mask where oral pustules occur, and avoiding all physical contact with pustules (by self and others). Draft licence conditions have been included to require the licence holder to: educate trial participants about the potential for transmission of the GMO to untreated people or animals, and possible adverse effects; instruct trial participants in precautions to minimise spread of the GMO; and exclude people from the trial if they are unwilling or unable to comply with these precautions.

314.

The applicant would require trial participants who develop GMO-related lesions to avoid all direct physical contact with individuals at risk of severe adverse reactions to VACV, which would further reduce the opportunity for transmission to people at greatest risk of harm from exposure to the GMO. Again, a requirement for trial participants to be informed of this measure and excluded from the trial if unwilling or unable to comply has been included as a draft licence condition. The risk related to transmission to at-risk individuals from an unrecognised pustule was assessed as a negligible to low risk, and is addressed in Section 2, above.

315.

In the event of a clinically-significant reaction to the GMO, the applicant has advised that study sites are to seek infectious disease expertise and immediately inform the international trial sponsor. SillaJen, Inc has made arrangements for VIG (recommended for treating some adverse reactions to VACV) to be provided to study sites in Australia within 24 hours of


Office of the Gene Technology Regulator request. A requirement for appropriate medical treatment to be provided to persons who are found to have been accidentally infected with the GMO has been included as a draft licence condition.

316.

Storage and transport, including of waste containing the GM virus, will be in accordance with relevant International Air Transport Association requirements and/or the Regulator’s guidelines. This will minimise exposure of other people and the environment to the GM virus and has been included in draft licence conditions.

317.

All waste generated at the clinical sites will be disposed of in accordance with standard clinical waste disposal practices. This would also minimise exposure of people and the environment to the GMO and has been included as a draft licence condition.

318.

Maintaining records of all GMO received, dispensed and destroyed will ensure all vials of the GMO are accounted for. Returning or destroying all GMO remaining when the study at each clinical site is complete will ensure it is not inadvertently released at a later time. These practices have been included as draft licence conditions.

3.2 Summary of draft licence conditions proposed to limit and control the release

319.

A number of licence conditions have been proposed to limit and control the proposed release based on the considerations discussed in subsection 3.1 above. These include requirements that:

 limit the release to a maximum of 75 trial participants inoculated with the GM viruses at designated clinical facilities over a 5 year period

 restrict the method of administration of the GMO to intratumoural inoculation

 restrict exposure of at-risk individuals (both patients and staff) by specific exclusion criteria

 require that the GMO be administered, and patients cared for, by trained clinical staff at hospital facilities in accordance with Universal Standard Precautions and ICH-GCP

11

, and that appropriate protective equipment is worn and used

 require that patients be educated about the potential for transmission of the GMO and instructed in precautions to minimise interpersonal spread

 require that additional precautions be developed and implemented to prevent interpersonal spread of the GMO within the clinical sites

 transport and store all GM vaccines in accordance with relevant regulations and guidelines 12

 dispose of all waste generated at clinical sites in accordance with standard disposal practices for infectious clinical waste

 require that contingency plans be in place to manage any exposure to the GM virus and treat any vaccinia-related illness that may eventuate

 destroy or return all unused GMO on completion of the study, and maintain records of all

GMO received, dispensed and destroyed.

11 The international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, guidelines for good clinical practice (ICH 1996)

12 The Gene Technology Regulator’s Guidelines for the Transport, Storage and Disposal of GMOs; IATA

Transportation Regulations



Section 4 Other risk management considerations

320.

All DIR licences issued by the Regulator contain a number of conditions that relate to general risk management. These include conditions relating to:

 applicant suitability;

 identification of the persons or classes of persons covered by the licence;



reporting structures, including a requirement to inform the Regulator is the applicant becomes aware of any additional information about risks to the health and safety of people or the environment; and

 a requirement that the applicant allow access to the trial sites by the Regulator, or persons authorised by the Regulator, for purpose of monitoring or auditing.

4.1 Applicant suitability

321.

In making a decision whether or not to issue a licence, the Regulator must have regard to the suitability of the applicant to hold a licence. Under section 58 of the Act, matters that the

Regulator must take into account include:

 any relevant convictions of the applicant (both individuals and the body corporate)

 any revocation or suspension of a relevant licence or permit held by the applicant under a law of the Commonwealth, a State or a foreign country

 the capacity of the applicant to meet the conditions of the licence

322.

The Regulator considered the suitability of the applicant when the application was received. The Regulator will reassess the suitability of CNS before making the decision whether or not to issue a licence for this application (DIR 140).

323.

If a licence were issued, the conditions would include a requirement for the licence holder to inform the Regulator of any circumstances that would affect their suitability.

324.

In addition, any applicant organisation must have access to a properly constituted

Institutional Biosafety Committee and be an accredited organisation under the Act.

4.2 Contingency plans

325.

If a licence is issued, the licence holder would be required to submit a contingency plan to the Regulator prior to conducting any dealings authorised by the licence. This plan must detail measures to be undertaken in the event of: a) the unintended release of the GMO, including spills outside of clinical sites, and exposure of or transmission to persons other than trial participants; and b) a person exposed to the GMO developing a severe adverse response.

326.

The licence holder would also be required to provide a method to the Regulator for the reliable detection of the presence of the GMOs and the introduced genetic materials in a recipient organism. This would be required within 30 days of the issue date of the licence.

4.3 Identification of the persons or classes of persons covered by the licence

327.

If a licence were to be issued, the persons covered by the licence would be the licence holder and employees, agents or contractors of the licence holder and other persons who are, or have been, engaged or otherwise authorised by the licence holder to undertake any activity in connection with the dealings authorised by the licence. Prior to commencing dealings at any clinical site, CNS would also be required to notify the Regulator of the participating organisation, and provide a list of people who will be covered, or the function or position where names are not known at the time.



4.4 Reporting requirements

328.

If issued, the licence would oblige the licence holder to immediately report any of the following to the Regulator:

 any additional information regarding risks to the health and safety of people or the environment associated with the trial

 any contraventions of the licence by persons covered by the licence

 any unintended effects of the trial

329.

The licence holder would also be obliged to submit an Annual Report within 90 days of the anniversary of the licence containing any information required by the licence, including the results of inspection activities.

4.5 Monitoring for Compliance

330.

The Act stipulates, as a condition of every licence, that a person who is authorised by the licence to deal with a GMO, and who is required to comply with a condition of the licence, must allow inspectors and other persons authorised by the Regulator to enter premises where a dealing is being undertaken for the purpose of monitoring or auditing the dealing.

331.

If monitoring activities identify changes in the risks associated with the authorised dealings, the Regulator may also vary licence conditions, or if necessary, suspend or cancel the licence.

332.

In cases of non-compliance with licence conditions, the Regulator may instigate an investigation to determine the nature and extent of non-compliance. The Act provides for criminal sanctions of large fines and/or imprisonment for failing to abide by the legislation, conditions of the licence or directions from the Regulator, especially where significant damage to health and safety of people or the environment could result.

Section 5 Conclusions of the consultation RARMP

333.

The risk assessment concludes that the proposed limited and controlled release of GM virus to take place in Australian hospitals, involving up to 75 trial participants and expected to run for up to five years, poses negligible to low risks to the health and safety of people or the environment as a result of gene technology.

334.

The risk management plan concludes that the identified negligible to low risks can be managed so as to protect the health and safety of people and the environment by imposing risk treatment measures. If a licence were to be issued, conditions are also proposed to limit the release to the size, locations and duration requested by the applicant as these were important considerations in establishing the context for assessing the risks.



Chapter 4 Proposed licence conditions

Interpretations and Definitions

1.

In this licence: a) unless defined otherwise in this licence, words and phrases used in this licence have the same meaning as they do in the Act and the Gene Technology Regulations

2001; b) words importing a gender include any other gender; c) words in the singular include the plural and words in the plural include the singular; d) words importing persons include a partnership and a body whether corporate or otherwise; e) references to any statute or other legislation (whether primary or subordinate) are a reference to a statute or other legislation of the Commonwealth of Australia as amended or replaced from time to time and equivalent provisions, if any, in corresponding State law, unless the contrary intention appears; f) where any word or phrase is given a defined meaning, any other part of speech or other grammatical form in respect of that word has a corresponding meaning; g) specific conditions prevail over standard conditions to the extent of any inconsistency.

2.

In this licence:

'Act' means the Gene Technology Act 2000 (Cth) or the corresponding State legislation under which this licence is issued.

Analytical facility means a laboratory or premises that perform testing and/or analysis on biological samples (eg. blood, tissue, cells, proteins, nucleotides) in Australia.

'Annual Report' means a written report provided to the Regulator within 90 days of each anniversary of issue of this licence containing all the information required by this licence to be provided in the Annual Report.

‘Dealings’

in relation to a GMO, means the following: a) conduct experiments with the GMO; b) import the GMO; c) transport the GMO; d) dispose of the GMO; and includes the possession, storage, supply or use of the GMO for the purposes of, or in the course of, a dealing mentioned in any of paragraphs (a) to (i).

'Destroy' , (or 'Destroyed' or 'Destruction' ) means, as the case requires, killed by one or more of the following methods: a) treatment with chemical disinfectant; b) autoclaving; c) high-temperature incineration; and d) any other methods used by Study Sites for disposal of infectious clinical waste.

Chapter 4 – Proposed licence conditions 57


Note: 'As the case requires' has the effect that, depending on the circumstances, one or more of these techniques may not be appropriate.

‘Excluded Persons’ means women who are known to be pregnant; persons with known significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or immunosuppressive medication; persons with an ongoing severe inflammatory skin condition requiring medical treatment; and persons with a history of severe eczema requiring prior medical treatment.

'GM' means genetically modified.

'GMOs' means the genetically modified organisms the subject of the dealings authorised by this licence.

‘

ICH-GCP’ means the International Council for Harmonisation of Technical Requirements for

Registration of Pharmaceuticals for Human Use - Guidelines for Good Clinical Practice .

‘ Material’ means non-biological material used in conjunction with the GMO, such as syringes, swabs, vials, gloves or for cleanup of spills.

'OGTR' means the Office of the Gene Technology Regulator.

'Personal Information' means information or an opinion (including information forming part of a database), whether true or not, and whether recorded in a material form or not, about an individual whose identity is apparent, or can reasonably be ascertained, from the information or opinion.

'Regulator' means the Gene Technology Regulator.

‘ Sample’

means any biological material collected from trial participants for subsequent analysis.

‘Serious adverse event’ means any untoward medical occurrence that at any dose:

 results in death;

 is life-threatening;

 requires inpatient hospitalisation or prolongation of existing hospitalisation;

 results in persistent or significant disability/incapacity;

 is a congenital anomaly/birth defect; or

 is a medically important event or reaction.

‘Study Site’

means a hospital in Australia at which trial participants are inoculated with the

GMO. Study Sites must be registered and licensed for the purposes of handling scheduled medicines and poisons as legislated through the Poisons Standard, and other relevant

Australian state or territory laws in effect at the time.

‘TGA GCP Guidelines’

means the TGA Note for Guidance on Good Clinical Practice designated CPMP/ICH/135/95.

‘WHO Universal Standard Precautions’ means World Health Organisation Universal precautions for the prevention of transmission of infectious agents in healthcare settings .



General conditions and obligations

3.

This licence does not authorise dealings with GMOs that are otherwise prohibited as a result of the operation of State legislation declaring areas to be GM, GM free, or both, for marketing purposes.

4.

This licence remains in force until March 2021 unless it is suspended, cancelled or surrendered. No dealings with the GMO are authorised during any period of suspension.

5.

The holder of this licence ('the licence holder') is Clinical Network Services Pty Ltd.

6.

The persons covered by this licence are the licence holder and employees, agents or contractors of the licence holder and other persons who are, or have been, engaged or otherwise authorised by the licence holder to undertake any activity in connection with the dealings authorised by this licence.

7.

To the extent that any activity by a trial participant may be considered to be a dealing for purposes of the Act, that dealing is authorised by this licence.

8.

The only dealings authorised by this licence are to: a) import the GMO; b) conduct the following experiments with the GMO: i.

administration of the GMO to trial participants by intratumoural injection; ii.

collection of samples that may reasonably be expected to contain the GMO from trial participants; and iii.

in vitro analysis of the samples mentioned in (b)(ii). c) transport the GMO; d) dispose of the GMO; and possession, storage, supply and use of the GMO in the course of any of these dealings.

Obligations of the Licence Holder

9.

The licence holder must immediately notify the Regulator in writing if any of the details of the contact person for the licence change.

Note: please address correspondence to ogtr.applications@health.gov.au.

Prior to issuing a licence, the Regulator considers suitability of the applicant to hold a licence.

The following conditions address ongoing suitability of the licence holder.

10.

The licence holder must, at all times, remain an accredited organisation in accordance with the Act and must comply with its instrument of accreditation.

11.

The licence holder must: a) inform the Regulator immediately in writing, of: i.

any relevant conviction of the licence holder occurring after the commencement of this licence; and ii.

any revocation or suspension of a licence or permit held by the licence holder under a law of the Australian Government, a State or a foreign country, being a law relating to the health and safety of people or the environment; and iii.

any event or circumstances occurring after the commencement of this licence that would affect the capacity of the holder of this licence to meet the conditions in it; and


Office of the Gene Technology Regulator b) provide any information related to the licence holder's ongoing suitability to hold a licence, if requested, within the stipulated timeframe.

The following conditions seek to ensure that persons conducting the dealings are aware of the licence conditions and appropriate processes are in place to inform people of their obligations.

12.

Before commencing the clinical trial with the GMO at each Study Site , the licence holder must provide the Regulator with: a) the names of all organisations and persons, or functions or positions of persons

(other than trial participants), who will be covered by the licence at that Study Site, with a description of their responsibilities; and

Note: Examples of functions or positions are ‘Principal Investigator’, ‘Clinical research assistant’ etc. b) details of how the persons covered by the licence will be informed of licence conditions;

Note: this may include training, labelling, contractual agreements with other organisations such as contract research organisations, clinical waste treatment providers and courier companies, etc. c) details of how the licence holder will ensure compliance with licence conditions at the Study Site over the period that dealings are being conducted at the Study Site.

Note: this may include a description of any contracts, agreements, or other enforceable arrangements.

13.

Any changes to the information required under Condition 12 must be communicated in

writing to the Regulator within 14 days of the changes occurring.

14.

The licence holder must inform any person covered by this licence, to whom a particular condition of this licence applies, of the following: a) the particular condition (including any variations of it); b) the cancellation or suspension of the licence; c) the surrender of the licence.

Note: Information required under Condition 14 may be provided to contractors who are

engaged solely for the transport and/or disposal of the GMOs through labelling the outermost container of the GMOs.

15.

Subject to condition 16, the licence holder must not permit a person covered by this

licence to conduct any dealing unless: a) the person has been informed of the licence conditions, including any variation of the licence; and b) the licence holder has obtained from the person a signed and dated statement that the person: i.

has been informed by the licence holder of the licence conditions including any variation of the licence; and ii.

has understood and agreed to be bound by the licence conditions, or its variations. c) the licence holder has trained the person in a manner which:


Office of the Gene Technology Regulator i.

enables the person to safely conduct the dealings in accordance with the conditions of this licence; and ii.

enables the person to meet the work practices and behavioural requirements for conducting the dealings in Medical facilities.

16.

The licence holder is not required to comply with any part of paragraph (b) or (c) of

Condition 15 in relation to the following classes of person:

a) personnel at Analytical facilities;

Note: The Licence holder must have processes in place to ensure that part (a) of

Condition 15 is met in relation to Analytical facilities, and that the Regulator is informed

as soon as reasonably possible if there is an unintentional release of the GMO, or if persons undertaking these dealings are exposed to the GMOs, at an Analytical facility

(as required by Condition 31).

b) contractors transporting the GMOs from the point of import directly to a central storage facility or Study Site, provided the consignment is: i.

clearly labelled to indicate (at a minimum) that it contains GMOs and is authorised under the Gene Technology Act 2000 through licence DIR 140; ii.

packaged and transported according to IATA requirements for class

UN 3373; and iii.

only to be transported within Australia from the point of import to the central

storage facility (named in, or notified in accordance with, Condition 25) or

directly to a Study Site. c) contractors engaged solely for transport and/or disposal of the GMOs within

Australia, or for export provided: i.

the GMOs are double contained; and ii.

the outermost container is labelled to indicate (at a minimum):

 that it contains GMOs;

 the contact details for the Licence Holder; and

 instructions to notify the Licence holder in case of an unintentional release of the GMOs; and

 where transport is for the purpose of disposal, that the GMOs must be destroyed by autoclaving, high-temperature incineration, chemical treatment or otherwise destroyed as clinical waste.

17.

The licence holder must: a) inform the persons covered by this licence that any Personal Information relevant to the administration and/or enforcement of the licence may be released to the

Regulator; and b) provide the Regulator, if requested, with copies of the signed and dated statements

referred to in Condition 15.

Provision of new information to the Regulator

Licence conditions are based on the risk assessment and risk management plan developed in relation to the application using information available at the time of assessment. The following condition requires that any new information that may affect the risk assessment is communicated to the Regulator.



18.

The licence holder must inform the Regulator, if the licence holder becomes aware of: a) additional information as to any risks to the health and safety of people, or to the environment, associated with the dealings authorised by the licence; or b) any contraventions of the licence by a person covered by the licence; or c) any unintended effects of the dealings authorised by the licence.

Note: The Act requires, for the purposes of the above condition, that: a) the licence holder will be taken to have become aware of additional information if he or she was reckless as to whether such information existed; and b) the licence holder will be taken to have become aware of contraventions, or unintended effects, if he or she was reckless as to whether such contraventions had occurred, or such unintended effects existed.

19.

If the licence holder is required to inform the Regulator under Condition 18, the

Regulator must be informed as soon as reasonably possible.

Obligations of persons covered by the licence

20.

Persons covered by this licence must not deal with the GMO except as expressly permitted by this licence.

21.

If a person is authorised by this licence to deal with the GMOs and a particular condition of this licence applies to the dealing by that person, the person must allow the Regulator, or a person authorised by the Regulator, to enter premises where the dealing is being undertaken, for the purposes of auditing or monitoring the dealing.

Limits and control measures

Note: This licence does not expressly authorise or prohibit any dealings or storage in certified physical containment facilities. Under the Act it is not an offence to deal with a GMO if the dealing is otherwise licenced or if it is an NLRD or an exempt dealing and it complies with all relevant statutory requirements.

Limits on the release

The following licence conditions maintain the risk assessment context within which the application was assessed by imposing limits on where and when experiments with the GMOs may be performed, and on other activities that can be undertaken.

22.

The GMO covered by this licence is JX-594, also known as Pexa-Vec, described in

Attachment A of the licence.

Note: Attachment A is not included in the draft licence as the GMO is described in Chapter 1 the RARMP.

23.

Details of each Study Site must be notified to the Regulator at least 7 days before commencement of dealings at that Study Site.

24.

All dealings permitted under this licence must be conducted within Study Sites, except for: a) import; b) storage; c) transport; and d) disposal.



25.

Prior to distribution to Study Sites within Australia, the GMO may only be stored at

Flinders Clinical Trial Services, Adelaide, South Australia or other distribution centres notified to the Regulator in writing.

26.

A maximum of 75 adults with Hepatocellular Carcinoma may be inoculated with the

GMO.

Controls on the Release

The following licence conditions manage the identified risks, and maintain the risk assessment context within which the application was assessed, by restricting exposure to the GMO.

Conduct of the clinical trial

27.

The licence holder must ensure that the trial is conducted according to ICH-GCP and

TGA GCP Guidelines and WHO Universal Standard Precautions.

28.

Before commencement of dealings at each Study Site, the licence holder must ensure that appropriate ‘Contact Precautions’ are developed to minimise interpersonal transmission of the

GMO from patients who present with GMO-related lesion to clinical staff and other patients.

These precautions must be based on a risk assessment and documented as Standard Operating

Procedures (SOPs). Both the risk assessment(s) and SOP(s) must be provided to the Regulator on request.

29.

The licence holder must ensure that Excluded Persons are excluded from directly handling the GMO, administering it to patients or caring for trial participants who have or may have GMO-related lesions

30.

Procedures must be in place to account for the contents of all vials containing GMO that are imported into Australia under this licence. The GMO must be accounted for from import to destruction or export, and records must be made available to the Regulator on request.

31.

If any of the events described in Condition 47 occur, the appropriate procedure(s) from

the Contingency Plan must be implemented.

Conditions relating to trial participants

32.

The licence holder and persons administering the GMO must ensure that exclusion criteria used in selecting trial participants include (but need not be limited to) the following:

Exclusion from the trial of persons: a) who are Excluded Persons; b) who experienced a severe systemic reaction or side effect as a result of a previous exposure to vaccinia virus ; and c) who are unable or unwilling to comply with the requirements listed in

Condition 33.

33.

The licence holder must ensure that trial participants are educated about the potential for transmission of the GMO to untreated people and animals and measures to prevent transmission, and obtain trial participants’ written agreement that: a) while undergoing treatment with the GMO, they will implement hygiene measures intended to prevent interpersonal transmission of the GMO, including but not limited to frequent hand washing with soap or hand disinfectant, respiratory hygiene and cough etiquette (for two weeks after the first round of treatment) and refraining from blood, tissue or organ donation; b) they will avoid direct physical contact with children under 12 months of age and

Excluded Persons, from the time of their first treatment with the GMO until after


Office of the Gene Technology Regulator the first follow-up visit to the treating hospital that occurs on or after day 8 postinoculation; c) should they develop GMO-related lesions during the study, they will, until such time as the lesions have healed:

 continue to avoid direct physical contact with children under 12 months of age and Excluded Persons;

 follow instructions provided by the treating hospital for disinfection of contaminated clothing, linens etc (e.g. laundering in hot water or treating with dilute bleach solution);

 keep skin lesions covered with a dressing;

 if oral lesions are present, wear a mask in the presence of others and refrain from sharing items such as toothbrushes and eating utensils; and

 prevent all direct physical contact (by people and animals) with lesions or with any potentially contaminated Material except where necessary for patient care;

 ensure persons caring for the lesions wear disposable gloves and wash or disinfect their hands immediately afterwards;

 seal used dressings and other Materials used in caring for the lesion in a primary container (e.g. a sealable plastic bag), place these within a secondary container provided by the Study Site, and store the secondary container such that it is inaccessible to children and animals until it is returned to the Study

Site;

 return the secondary container referred to above to the Study Site for disposal as clinical waste.

34.

Records of trial participants’ agreements as required under Condition 33 must be made

available to the Regulator on request.

35.

The licence holder must ensure that persons are not enrolled in the trial without first ascertaining whether or not they are likely to come into contact with children under 12 months of age or Excluded Persons. This must be documented in writing and records made available to the Regulator on request.

36.

Trial participants must be assessed for the presence of GMO-related lesions at their first follow-up visit to the Study Site that occurs on or after the 8 th

day after their first round of treatment with the GMO. If any GMO-related lesion is found, the trial participant must be informed that they have a GMO-related lesion and to continue to avoid children under 12 months of age and Excluded Persons.

37.

The licence holder must ensure trial participants are provided with a supply of secondary containers appropriate for transporting waste back to the treating hospital, labelled to indicate that it contains GMOs; that it must be destroyed by autoclaving, high-temperature incineration, chemical treatment or as clinical waste; and with contact details for the Study Site.



Work practices at Study Sites

38.

When undertaking a dealing with a GMO at a Study Site, including storage and disposal, persons covered by this licence must employ work practices and behaviours which: a) ensure containment of the GMO; and b) will not pose a risk to the health and safety of people and the environment.

39.

For the purposes of Condition 38, the work practices and behaviours must include, but

are not limited to, the following: a) all inoculations of the GMO must be administered by suitably qualified and trained medical staff. b) when dispensing and administering the GM virus, clinical trial staff must: i.

use a Class II biosafety cabinet to prepare the inoculum; ii.

wear personal protective equipment including a laboratory coat or gown, gloves, eye protection and mask; iii.

follow institutional procedures for safe handling of sharps. c) if a trial participant presents at a Study Site with a GMO-related lesion, the

‘Contact Precautions’ SOPs developed for the Study Site to minimise interpersonal transmission of the GMO from these patients must be implemented.

Patient samples containing the GMO

40.

Where a sample taken from a trial participant contains the GMO, or may reasonably be expected to contain the GMO, the sample must be treated as if it were the GMO.

41.

Where laboratory analysis of Samples that may reasonably be expected to contain the

GMO occurs in Australia, it may only take place in Analytical Facilities.

Storage of the GMO

42.

Storage of the GMO at individual Study Sites, Flinders Clinical Trial Services and any

other distribution centre notified to the Regulator under Condition 25 must be in accordance

with Part 2.1 of the Regulator’s Guidelines for the Transport, Storage and Disposal of GMOs, as current at the time of storage.

43.

Samples that may reasonably be expected to contain the GMO that are stored in

Analytical Facilities, and waste stored in trial participants’ homes must be stored under two levels of containment. The outermost container must be unbreakable and clearly labelled to indicate that it contains or may contain a GMO.

Note: In the case of a small storage unit such as a fridge, freezer or liquid nitrogen container, the secondary container may be the storage unit.

Transport and Disposal of the GMO

44.

Transport of the GMO must be in accordance with Part 1.2 of the Regulator’s

Guidelines for the Transport, Storage and Disposal of GMOs in force at the time of transportation, unless: a) the GMO is in its original packaging, in which case the requirement for

Decontamination of Containers (items 1.2.1.6 and 1.2.1.7 in version 1.1 of these guidelines) is exempted; or b) the transport is by contractors transporting the GMO from the point of import to

Flinders Clinical Trial Services or directly to a Study Site, and the transport is in

accordance with Condition 16 (b); or


Office of the Gene Technology Regulator c) the transport is by contractors for the purpose of disposal and is in accordance with

Condition 16 (c);

d) waste potentially contaminated with the GMO is being returned to the treating hospital by a trial participant.

45.

Decontamination of the GMO or waste containing the GMO must be by autoclaving, high temperature incineration, chemical treatment or any other method approved in writing by the Regulator. Decontamination by commercial waste contractors may be by methods used by

Study Sites for disposal of infectious clinical waste.

46.

Unless covered by another authorisation, the GMO and any Material or waste containing the GMO must be destroyed or exported, on or before expiration of the licence.

Contingency Plans

47.

Before any trial participant is inoculated with the GMO, a written Contingency Plan must be submitted to the Regulator detailing measures to be taken in the event of: a) the unintentional release of the GMO, such as a spill outside of a Study Site; b) exposure of, or transmission to, persons other than trial participants; and c) a person exposed to the GMO developing a severe adverse response, including those known to result from infection with vaccinia virus .

48.

The Contingency Plan must include details of procedures to: a) ensure the Regulator is notified as soon as reasonably possible after the licence holder becomes aware of the event; and b) implement the following measures if there is a spill of the GMO, such as during import, transport, storage or disposal: i.

contain the GMOs to prevent further dispersal; and ii.

decontaminate the exposed area with an appropriate chemical disinfectant effective against the GMOs. c) implement the following measures if the GMO is transmitted to people other than trial participants: i.

provide appropriate medical treatment to affected persons as necessary ii.

prevent the further spread or persistence of the GMO; and iii.

identify the pathway of exposure. d) implement the following measures if a person exposed to the GMO exhibits symptoms of a severe adverse response to vaccinia virus : i.

provide appropriate medical treatment to the affected person; and ii.

prevent the spread or persistence of the GMO.

Additional Reporting Requirements

Notice of commencement and completion of the trial

49.

The licence holder must notify the Regulator of the following: a) the first inoculation of the first trial participant at each Study Site, within 7 days of the event; and b) the final inoculation of the last trial participant at each Study Site, within 30 days of the decision to cease inoculations at the Study Site.



Annual

R

eport

50.

The licence holder must provide an Annual Report to the Regulator that includes: a) the number of trial participants inoculated with the GMO under this licence in the previous 12 months; and b) details of any serious adverse events linked to exposure to the GMOs.

Testing methodology

51.

The licence holder must provide the Regulator with a written document describing an experimental method that is capable of reliably detecting the presence of the GMO and the presence of the genetic modifications described in this licence in a recipient organism. The detection method should be capable of reliably distinguishing between GMO described in this licence and the parent organism. The document must be provided prior to commencing any dealings authorised by this licence.



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DOCX format

Risk Assessment and

Risk Management Plan for

Consultation Version

Clinical trial of a genetically modified virus for treatment of liver cancer

Applicant: Clinical Network Services Pty Ltd

December 2015

Summary of the Risk Assessment and Risk

Management Plan

(Consultation Version) for

Licence Application No. DIR 140

Introduction

The application

Risk assessment

Risk management plan

Table of Contents

Abbreviations

Chapter 1 Risk assessment context

Section 1 Background

Section 2 Regulatory framework

Section 3 Proposed Dealings

Section 4 The parent organism

Section 5 The GMO – nature and effect of the genetic modification

Section 6 The receiving environment

Section 7 Relevant Australian and international approvals

Chapter 2 Risk assessment

Section 1 Introduction

Section 2 Risk Identification

Section 3 Risk characterisation

Section 4 Uncertainty

Section 5 Risk Evaluation

Chapter 3 Risk management

Section 1 Background

Section 2 Risk treatment measures for substantive risks evaluated as requiring treatment

Section 3 General risk management

Section 4 Other risk management considerations

Section 5 Conclusions of the consultation RARMP

Chapter 4 Proposed licence conditions

Interpretations and Definitions

General conditions and obligations

Obligations of the Licence Holder

Provision of new information to the Regulator

Obligations of persons covered by the licence

Limits and control measures

Limits on the release

Controls on the Release

Additional Reporting Requirements

Notice of commencement and completion of the trial

Annual

eport

Testing methodology

References

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